[Federal Register Volume 88, Number 104 (Wednesday, May 31, 2023)]
[Rules and Regulations]
[Pages 34756-34779]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-11477]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 174

[EPA-HQ-OPP-2019-0508; FRL-7261-04-OCSPP]
RIN 2070-AK54


Pesticides; Exemptions of Certain Plant-Incorporated Protectants 
(PIPs) Derived From Newer Technologies

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: The Environmental Protection Agency (EPA) is exempting a class 
of plant-incorporated protectants (PIPs) that have been created using 
genetic engineering from certain registration requirements under the 
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and from 
the requirements to establish a tolerance or tolerance exemption for 
residues of these substances on food or feed under the Federal Food, 
Drug, and Cosmetic Act (FFDCA). Specifically, EPA is finalizing its 
exemptions as described in its October 2020 proposal for PIPs now 
termed ``PIPs created through genetic engineering from a sexually 
compatible plant'' and ``loss-of-function PIPs,'' finalizing the 
process through which the Agency determines their eligibility for 
exemption, and finalizing the associated recordkeeping requirements. 
This set of exemptions reflects the biotechnological advances made 
since 2001, when EPA first exempted PIPs derived through conventional 
breeding and excluded from the exemptions those PIPs that are created 
through biotechnology. EPA

[[Page 34757]]

anticipates that today's exemptions will benefit the public by ensuring 
that human health and the environment are adequately protected, while 
also reducing the regulatory burden for the regulated community. These 
exemptions may also result in increased research and development 
activities, commercialization of new pest control options for farmers, 
particularly in minor crops, and increase the diversity of options for 
pest and disease management, which could provide environmental 
benefits.

DATES: This final rule is effective on July 31, 2023.

ADDRESSES: The docket for this action, identified under docket 
identification (ID) number EPA-HQ-OPP-2019-0508, is available at 
https://www.regulations.gov. Additional instructions on visiting the 
docket, along with more information about dockets generally, is 
available at https://www.epa.gov/dockets. For the latest status 
information on EPA/DC services and docket access, visit https://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Amanda Pierce, Biopesticides and 
Pollution Prevention Division (7511P), Office of Pesticide Programs, 
Environmental Protection Agency, 1200 Pennsylvania Ave. NW, Washington, 
DC 20460-0001; main telephone number: (202) 948-3693; email address: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Executive Summary

A. Does this action apply to me?

    You may be potentially affected by this action if you are a 
developer or registrant of a PIP. This action also may affect any 
person or company who might petition the Agency for a tolerance or an 
exemption from the requirement of a tolerance for any residue of a PIP. 
The following list of North American Industrial Classification System 
(NAICS) codes is not intended to be exhaustive, but rather provides a 
guide to help readers determine whether this document applies to them. 
Potentially affected entities may include:
     Pesticide and Other Agricultural Chemical Manufacturing 
(NAICS code 325320), e.g., pesticide manufacturers or formulators of 
pesticide products, importers or any person or company who seeks to 
register a pesticide or to obtain a tolerance for a pesticide.
     Crop Production (NAICS code 111), e.g., seed companies.
     Colleges, universities, and professional schools (NAICS 
code 611310), e.g., establishments of higher learning which are engaged 
in development and marketing of PIPs.
     Research and Development in the Physical, Engineering, and 
Life Sciences (except Nanobiotechnology) (NAICS code 541714), e.g., 
biotechnology research and development laboratories or services.
    If you have any questions regarding the applicability of this 
action to a particular entity after reading the regulatory text, 
consult the technical person listed under FOR FURTHER INFORMATION 
CONTACT.

B. What action is the Agency taking?

    This rule establishes exemptions under the Federal Insecticide, 
Fungicide, and Rodenticide Act (FIFRA), 7 U.S.C. 136 et seq. and 
codified at 40 CFR 174.26 and 174.27 and for the residues of such PIPs 
under the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a 
and codified at 40 CFR 174.541 for certain PIPs that are created in 
plants using biotechnology. In this final rule, the term ``exemption'' 
is applied to actions under both of these statutes. (EPA notes that 
this action only exempts qualifying PIPs from regulation under FIFRA 
and the need to establish a tolerance for residues of qualifying PIPs 
under section 408(e) of the FFDCA; other statutory or regulatory 
requirements may still apply, e.g., State, Tribal, or local 
requirements). This rule provides criteria and definitions that 
identify the two groups of PIPs that are exempted through this action, 
called ``PIPs created through genetic engineering from a sexually 
compatible plant'' and ``loss-of-function PIPs,'' and codifies the 
process through which the Agency determines their eligibility for 
exemption. The rule also codifies the recordkeeping requirements for 
exempted PIPs, and the preamble, along with the accompanying Response 
to Comments document (Ref. 1), addresses the public comments that the 
Agency received on the proposed rule (85 FR 64308; October 9, 2020; 
FRL-10014-10) (Ref. 2) during the public comment period. EPA's 
responses to those comments are summarized in Unit IV. and in the 
Response to Comments document (Ref. 1) that is available in docket for 
this action.

C. What is the Agency's authority for taking this action?

    This action is being taken under the authority of FIFRA section 25 
(7 U.S.C. 136w) and FFDCA section 408(e) (21 U.S.C. 346a(e)). FIFRA 
section 25(a)(1) authorizes EPA to issue regulations to carry out the 
provisions of FIFRA in accordance with certain procedures prescribed in 
that section. In addition, FIFRA section 25(b) allows EPA to promulgate 
regulations to exempt from the requirements of FIFRA any pesticide 
which the Administrator determines is ``of a character which is 
unnecessary to be subject to [FIFRA] in order to carry out the purposes 
of [FIFRA].'' FFDCA section 408(e) authorizes EPA to initiate actions 
to establish tolerances or exemptions for pesticide chemical residues 
that meet the safety standard. Section 408 of the FFDCA is focused on 
human risk. To make a safety finding under FFDCA to support a tolerance 
or exemption for pesticide residues on food, EPA considers, among other 
things: the toxicity of the pesticide and its metabolites and 
degradates, aggregate exposure to the pesticide in foods and from other 
sources of exposure, and any special risks posed to infants and 
children. The potential for pesticide exposure through food from food-
producing animals that consume feed is part of the human health risk 
assessment used in EPA's FFDCA determinations. Risk to non-target 
organisms and risk associated with occupational exposure is evaluated 
under FIFRA. A more detailed discussion of EPA's statutory authority is 
available in Units III.A., III.B., and III.C. of the proposed rule (85 
FR 64313-64314, October 9, 2020) (Ref. 2).

D. Why is EPA taking this action?

    Recent advances in genetic engineering offer not only precise means 
by which genes coding for pesticidal substances can be inserted into a 
plant genome but also allow for modifications of genes that already 
exist within a plant. Due to the sophistication of these technologies, 
PIPs can now be created through genetic engineering that are virtually 
indistinguishable from those created through conventional breeding. 
These advances also allowed EPA to develop specific exemption criteria 
to circumscribe PIPs created through genetic engineering that pose no 
greater risk than the PIPs created through conventional breeding that 
have been exempt since 2001.
    This rule is an effort to implement the policy goals articulated by 
multiple administrations to improve, clarify, and streamline 
regulations of biotechnology, beginning with the White House Office of 
Science and Technology Policy in a policy statement in 1986 on the 
``Coordinated Framework for the Regulation of Biotechnology'' (51 FR 
23302; June 26, 1986), the update to the Coordinated Framework in 2017 
(Ref. 3), Executive Order 13874 (84 FR 27899, June 11, 2019) on 
``Modernizing the

[[Page 34758]]

Regulatory Framework for Agricultural Biotechnology Products,'' and 
more recently, Executive Order 14801 (87 FR 56849, September 12, 2022) 
on ``Advancing Biotechnology and Biomanufacturing Innovation for a 
Sustainable, Safe, and Secure American Bioeconomy.''

E. What are the estimated incremental impacts?

    EPA has evaluated the potential incremental impacts of the proposed 
exemptions in the document entitled ``Cost Analysis For the Final Rule 
Exempting Certain Plant-Incorporated Protectants (PIPs) from 
Registration'' (Ref. 4), which is available in the docket and is 
briefly summarized here.
1. Benefits
    This rule reduces the regulatory hurdle (primarily cost) of getting 
certain PIPs to market. Accordingly, this rule is likely to encourage 
more research and development in this area of biotechnology and better 
enable firms of all sizes to engage in the development of these types 
of PIPs. Entities producing products designed for minor crops may not 
support markets large enough to warrant fixed registration costs. These 
entities may feel the most regulatory relief as a result of this rule.
    Crop varieties modified for greater pest and disease resistance 
could increase the diversity of options for pest and disease 
management, which in turn, could provide environmental benefits and 
lower exposure for workers who apply pesticides. Growers may also 
benefit because they will have more tools available to combat pest 
pressures.
    The rule is estimated to reduce overall registration costs (fees 
plus information and data requirement costs) to developers of ``PIPs 
created through genetic engineering from a sexually compatible plant'' 
and ``loss-of-function PIPs.'' On a per-product basis, the cost savings 
are estimated to range from $472,000-$886,000 using a 3% discount rate 
on future maintenance fees. A range of cost savings is provided because 
``loss-of-function PIPs'' have fewer data requirements than ``PIPs 
created through genetic engineering from a sexually compatible plant'' 
and are not required to submit a request for EPA confirmation (thereby 
avoiding an M009 PRIA fee). Therefore, the savings to developers for 
``loss-of-function PIPs'' is higher.
    On an annual basis, the Agency estimates that anywhere from one to 
ten PIPs may be eligible for exemption. This upper and lower bound 
estimate is provided because, while the number of PIPs eligible for 
exemption is unknown, EPA has determined that it is likely to be 
greater than one. This is an increase from the estimate provided in the 
cost analysis for the proposed rule, which only included savings from 
one PIP. Accordingly, EPA estimates the annual savings of this rule to 
range from $472,000-$8,856,000 using a 3% discount rate on future 
maintenance fees (the lower bound represents one PIP per year and the 
upper bound represents ten PIPs per year will be eligible for 
exemption).
    Of the entities likely to develop the types of PIPs this rule 
exempts, EPA currently estimates that approximately 80% are small 
entities. These cost savings would be realized as EPA approval of new 
active ingredients are sought. These exemptions are likely to remove a 
potential barrier to market entry for small entities because the 
monetary investment via Pesticide Registration Improvement Act (PRIA) 
fees and information and data requirement costs are substantially 
reduced from what would have been required under the registration 
process (in the absence of this rulemaking).
2. Costs
    The costs of the rule includes costs imposed on developers and 
differences to societal welfare as a result of the rulemaking. The cost 
imposed on developers of PIPs include the costs to:
     Meet the requirements of the eligibility determination 
process per 40 CFR 174, subpart E;
     Maintain records related to the requirements of the 
eligibility determination for five years starting from the effective 
date of the exemption per 40 CFR 174.73; and
     Report any information regarding adverse effects on human 
health and the environment alleged to be caused by the PIP be reported 
to EPA per 40 CFR 174.71.
    These costs are outlined in the cost analysis for the final rule. 
In consideration of the benefits and costs of the rule, the net effect 
is a cost savings to regulated entities. This is because the 
requirements to meet the eligibility determination process are less 
than what is required under registration. In the baseline, or no rule 
scenario, developers must maintain records related to registration; in 
the rule scenario, developers must similarly maintain records related 
to the exemption and exemption eligibility determination process--the 
net effect therefore of this requirement on developers is zero. In both 
the baseline, or no rule scenario, and in the rule scenario, developers 
are subject to the adverse effects reporting requirement--the net 
effect therefore of this requirement on developers is also zero.
    The costs of the rule also include differences to societal welfare 
as a result of the rulemaking, which in this case would be any 
increased risk to human health or the environment from the change in 
regulatory oversight from the rule. There are little to no costs such 
as these anticipated by the rule because the criteria for qualification 
were chosen to minimize any such risks. EPA has concluded that adverse 
effects due to aggregate exposure to residues of pesticidal substances 
from ``PIPs created through genetic engineering from a sexually 
compatible plant'' through the dietary, non-food oral, dermal and 
inhalation routes are highly unlikely.

II. Summary of the Proposed Rule

    In a proposed rule issued in October 2020 (Ref. 2), EPA proposed 
to:
    1. Exempt ``plant-incorporated protectants based on sexually 
compatible plants created through biotechnology'' (40 CFR 174.26) from 
the requirement of a tolerance under FFDCA and from certain 
registration requirements under FIFRA, except for the following 
requirements: a proposed requirement of recordkeeping (40 CFR 174.73), 
a proposed eligibility determination process (40 CFR 174, subpart E), 
and the existing adverse effects reporting requirement for exempt 
plant-incorporated protectants (40 CFR 174.71);
    2. Clarify the general qualifications for exemption for plant-
incorporated protectants at 40 CFR 174.21;
    3. Clarify how the proposed exemption relates to the existing 
exemption for plant-incorporated protectants derived from sexually 
compatible plants at 40 CFR 174.25; and
    4. Allow the existing inert ingredient exemption at 40 CFR 174.705 
to include biotechnology.
    Unit VI. of the proposed rule explained the proposed exemption for 
``PIPs based on sexually compatible plants created through 
biotechnology,'' detailed the rationale underlying that proposal, and 
described associated definitions that were proposed for codification or 
amendment (85 FR 64308) (Ref. 2), and also described the two primary 
considerations that EPA believed together would constitute the basis 
for meeting the FIFRA section 25(b)(2) standard for exemption (the 
pesticidal substance is found in plants that are sexually compatible 
with the recipient plant; and limitations on the expression profile). 
Also described were the details of the proposed eligibility 
determination process, and a proposed recordkeeping requirement for

[[Page 34759]]

exempted PIPs listed under 40 CFR 174.21(d).
    In addition, EPA proposed edits to 40 CFR 174.21 to clarify the 
applicability of this framework to other PIP exemptions and EPA 
proposed to clarify the relationship between the proposal on ``PIPs 
based on sexually compatible plants created through biotechnology'' and 
the exemptions currently at 40 CFR 174.25, ``Plant-incorporated 
protectant from sexually compatible plant,'' and 40 CFR 174.508, 
``Pesticidal substance from sexually compatible plant; exemption from 
the requirement of a tolerance.'' EPA also proposed to allow the 
existing inert ingredient exemption at 40 CFR 174.705 to include inert 
ingredients created using biotechnology so long as they still meet the 
existing criteria.

III. Summary of the Final Rule

    In this action, EPA is finalizing the following:
    1. An exemption for a category of ``PIPs created through genetic 
engineering from a sexually compatible plant;''
    2. An exemption for a category of ``loss-of-function PIPs;''
    3. An exemption eligibility determination process for certain 
exempted PIPs, including exemption specific information required for 
submission to support the exemption;
    4. Recordkeeping requirements for certain exempted PIPs;
    5. Clarifications for the general qualifications for exemption at 
40 CFR 174.21;
    6. Clarifications on the relationship between the existing 
exemptions for PIPs from sexually compatible plants and the newly 
issued exemption for ``PIPs created through genetic engineering from a 
sexually compatible plant;'' and
    7. Allow the existing inert ingredient exemption at 40 CFR 174.705 
to include genetic engineering.

A. Exemption for ``PIPs Created Through Genetic Engineering From a 
Sexually Compatible Plant''

    This rule exempts from all FIFRA requirements, except for the 
adverse effects reporting requirements at 40 CFR 174.71, the 
recordkeeping requirements at 40 CFR 174.73 (as specified in 40 CFR 
174.21(d)), and the eligibility determination process outlined in 
subpart E, ``PIPs created through genetic engineering from a sexually 
compatible plant.'' In the proposed rule, PIPs described under 40 CFR 
174.26 were termed ``PIPs based on sexually compatible plants created 
through biotechnology.'' In this final rule, EPA has updated the name 
of the PIPs described under 40 CFR 174.26 to be ``PIPs created through 
genetic engineering from a sexually compatible plant'' based on public 
comment, as discussed in Unit IV.A.3.
1. Associated Definitions
    The language describing the exemption appears in 40 CFR 174.26. 
Pertinent definitions associated with the exemption are found in 40 CFR 
174.3 and include:
    ``Gene'' and other grammatical variants such as ``genic,'' means a 
unit of heritable genetic material that is comprised of the genetic 
material necessary for the production of a substance.
    The definition for ``gene'' was revised from the proposal to remove 
the word ``functional'' before the phrase ``unit of heritable genetic 
material that is comprised of the genetic material necessary for the 
production of a substance.'' EPA made this change because loss-of-
function traits are created by targeting a gene underlying an unwanted 
trait by reducing or removing the gene's function. While the gene may 
no longer be functional, structurally it is still a gene. Although this 
is commonly understood in the scientific community, removing the word 
``functional'' from the definition may reduce confusion over the 
relationship between the definition of ``gene'' and ``loss-of-function 
PIPs.'' Therefore, for the reasons outlined, EPA removed the word 
``functional'' from the definition of ``gene.'' As discussed in Unit 
V.A. of the proposal, the two genic regions relevant to the exemptions 
under 40 CFR 174.26 are the coding and regulatory regions. These 
regions are delineated through use of the phrase ``genetic material 
necessary for the production,'' which as defined under 40 CFR 174.3 
means both ``genetic material that encodes a substance or leads to the 
production of a substance; and regulatory regions. It does not include 
noncoding nonexpressed nucleotide sequences.'' ``Noncoding, 
nonexpressed nucleotide sequences'' is also defined under 40 CFR 174.3 
and includes examples such as linkers, adapters, homopolymers, and 
sequences of restriction enzyme recognition sites (further discussed in 
the context of these exemptions in Unit IV.B.1.).
    ``Genetic engineering'' means the modification of the genome of an 
organism using recombinant, synthesized, or amplified nucleic acids or 
other techniques excluded from the definition of conventional breeding. 
``Genome'' is a defined term in 40 CFR 174.3 which means ``the sum of 
the heritable genetic material in the plant, including genetic material 
in the nucleus and organelles.'' EPA believes the use of the defined 
word ``genome'' in the ``genetic engineering'' definition would capture 
genetic engineering edits resulting in modifications to the proteome or 
transcriptome that are stably heritable.
    As discussed in Unit IV.A.2., EPA received a comment suggesting a 
definition for ``biotechnology.'' However, for consistency across the 
Coordinated Framework, the Agency chose to instead define ``genetic 
engineering.'' EPA used the two phrases synonymously in its proposed 
rule and therefore does not consider the change from ``biotechnology'' 
to ``genetic engineering'' to be substantive. For additional discussion 
on maintaining consistency across the Coordinated Framework for 
exemptions of products derived from genetic engineering, see Unit 
III.H.: ``Alignment of the proposed rule with USDA's amendment to 7 CFR 
340'' of the Response to Comments document in the docket associated 
with this rulemaking.
    ``Native allele'' means a variant of a native gene that is 
identified in the genetic diversity of plants sexually compatible with 
the recipient plant.
    ``Native gene'' means a gene that is identified in the recipient 
plant or source plants that are sexually compatible with the recipient 
plant. It does not include genes introduced through genetic engineering 
from a source organism that is not sexually compatible with the source 
plant.
    The definition for ``native gene'' was revised from the proposal 
based on public comment (Unit IV.A.1.). In the proposal, rather than 
specifically excluding genes introduced through recombinant DNA or 
similar techniques from a non-sexually compatible source organism, EPA 
used the term ``never derived.'' EPA received comment suggesting that a 
greater focus on excluding transgenes (i.e., genes introduced from non-
sexually compatible organisms) may aid in clarity and in turn reduce 
uncertainty around genes originating through natural horizontal gene 
transfer. EPA agreed with the suggestion and revised the definition to 
state EPA's intent more explicitly as outlined in the proposed rule 
(i.e., to exclude substances that conventional plant breeders do not 
have experience with, such as a bacterial endotoxin not historically 
found in a food plant). Screening practices and analyses performed as 
part of the standard conventional breeding process serve to eliminate 
plants that raise safety, quality or performance concerns. By limiting 
exempt substances to those

[[Page 34760]]

in which conventional plant breeders have experience, EPA can have 
confidence that these conventional plant breeding practices would still 
be protective for substances of exempt PIPs.
    In addition, EPA revised the definition in 40 CFR 174.3 for 
``Sexually compatible.'' In the proposed definition EPA stated that ``a 
viable zygote can be formed.'' This phrase was minorly revised to state 
``plants must be capable of forming a viable zygote'' for clarity.
2. Exemption Criteria
    PIPs that are created through genetic engineering but that could 
have otherwise been created through conventional breeding are exempt 
(40 CFR 174.26). The exemption criteria and associated definitions 
circumscribe PIPs that are created through genetic engineering using 
knowledge of nucleotide sequences in sexually compatible source plants 
to re-create a native allele or other functional nucleotide sequence 
identical to that which is found in a source plant. This would enable 
the use of genetic engineering of clonally-propogated cultivars of 
crops such as potato, grape, tree fruits, etc., to recreate pesticidal 
alleles found in sexually compatible cultivars or crop wild relatives. 
The exemption specifies criteria regarding the types of modifications 
that are allowed to be made to ensure that the exempt PIPs are 
characteristic in identity and in expression profile to those found in 
conventionally bred plants, and are therefore substances with which 
conventional plant breeders and conventional plant breeding screening 
methods have experience.
    The scope of ``PIPs created through genetic engineering from a 
sexually compatible plant'' is delineated in 40 CFR 174.26(a). The 
regulatory text identifies two overarching categories that specify what 
will qualify as an exempt PIP pesticidal substance: (1) The insertion 
of new genetic material and (2) The modification of existing genetic 
material.
    The provision at 40 CFR 174.26(a)(1) allows for insertions of new 
genetic material into the recipient plant so long as the genetic 
material is a native gene that is found in the sexually compatible 
plant population of that plant. This category requires that the entire 
pesticidal substance (e.g., amino acid sequence for proteinaceous PIPs) 
that is created from the native gene be identical to that produced in 
the source plant. 40 CFR 174.26(a)(1) was revised from the proposed 
text to include a criterion related to inserted regulatory regions. 40 
CFR 174.26(a)(1) now requires that any regulatory regions inserted as 
part of the native gene be identical to the regulatory regions of the 
native gene identified in the source plant. This change was made in 
response to comments EPA received stating that the proposed criterion 
related to expression profile (proposed 40 CFR 174.26(b)) was unclear 
(Units IV.C.2. and IV.E.4.b.). In response to these comments, EPA 
instead now provides specific criteria at codified 174.26(a)(1) related 
to the types of modifications that may impact expression. EPA is aware 
that intronic regions of genes may exhibit regulatory functions, but 
EPA does not expect that all introns necessarily need to be inserted as 
part of a native gene. Therefore, when describing the criterion related 
to identical sequences in the regulatory regions, EPA used the phrase 
``regulatory regions inserted as part of the native gene,'' to specify 
that the criterion only applies to those regulatory regions that are 
ultimately inserted as part of the native gene (i.e., it is not 
required that all regulatory regions be inserted, but those that are 
inserted must meet the criterion).
    The final text in 40 CFR 174.26(a)(1) was revised from what was in 
the proposed text to remove the clause ``into a non-genic location'' in 
the phrase ``A native gene is engineered into a non-genic location of 
the recipient plant genome [. . .].'' In the proposal, EPA stated that 
this phrase was intended to preclude the insertion of the native gene 
into an existing gene to prevent the production of a novel substance 
(e.g., a partial or modified substance) by the existing gene. However, 
upon further evaluation of this clause, prompted by public comment 
(Response to Comments document Unit III.A.3.), EPA determined that this 
restriction is not necessary as any novel substance that would be 
produced as a result of a fusion with the inserted PIP gene (i.e., 
through the creation of a novel open reading frame), would not meet the 
exemption under 40 CFR 174.26.
    The provision at 40 CFR 174.26(a)(2) describes permissible 
modifications to the existing genetic material in the recipient plant. 
40 CFR 174.26(a)(2) allows for modifications of the existing native 
gene to match corresponding polymorphic sequence(s) in a native allele 
of that gene using a single source plant as a template. Polymorphisms 
are variants of a gene sequence that are shared between native alleles. 
These genetic variations may be composed of single nucleotides (i.e., 
Single nucleotide polymorphisms (SNPs)) or larger DNA segments and they 
are found at the same locus within the genetic sequence of two or more 
native alleles. In some cases, enhanced pesticidal properties of a gene 
product can be attributed to one or more of these genetic variations 
within a native gene (Refs. 5, 6). The final rule (see 40 CFR 
174.26(a)(2)) allows developers to utilize their knowledge of specific 
polymorphisms in regulatory and coding regions of native alleles to 
make changes to the native gene in their recipient plant. The phrase 
``using a single source plant as a template'' in the provision limits 
the number of source plants for the polymorphic sequences to one. For 
example, it is not permissible to modify the polymorphic sequence of a 
native gene (in the recipient plant) to match a polymorphic sequence 
found in the native allele of a source plant and also modify a second 
polymorphic sequence in the native gene to match a sequence found in 
the native allele of a different source plant. This requirement is 
because EPA believes that increasing the amount of plants used as 
source plants for a single PIP may also lead to an increase in the 
likelihood that the substance is altered to something that plant 
breeders may not have experience. The second part of the phrase ``as a 
template'' indicates that the polymorphism that is engineered into the 
recipient plant must be identical in sequence to that which is found in 
the native allele of the source plant.
    The final rule (see 40 CFR 174.26(a)(2)) differs from what was 
proposed at 40 CFR 174.26(a)(2)(ii) in that EPA previously proposed to 
require that modifications resulting in a native allele produce a 
pesticidal substance identical to that produced in the source plant. 
The exemption category at 40 CFR 174.26(a)(2) is promulgated in 
response to comments received indicating that the proposed exemption 
categories were too narrow in that they do not capture the full extent 
of genetic variation that can occur in plants (Unit IV.C.1.). While the 
final text in 40 CFR 174.26(a)(2) does not require the entire substance 
to be identical to a substance found in the sexually compatible 
population of the recipient plant, it does require the individual 
polymorphism(s) to have been identified. By requiring the polymorphic 
sequences to be identical, this new exemption category allows the 
Agency to capture more of the possible genetic variation that can occur 
in plants, while staying within the bounds of what could have been 
achieved through conventional breeding and what was proposed.
    EPA acknowledges that the genetic variation that is observed in 
plants has the potential to be greater than what is captured at 40 CFR 
174.26(a). Therefore, the Agency intends to revisit the

[[Page 34761]]

question of capturing a broader range of genetic variation under 40 CFR 
174.26 in the future; a new rulemaking process that would be initiated 
by the Agency if, for example, new scientific information becomes 
available or if prompted by an interested party through an Agency 
inquiry, e.g., based on a specific PIP product. Importantly, any new 
categories of exempt PIPs that would be added to 40 CFR 174.26 through 
this process in the future: (1) Would be required to fall within the 
previously defined scope of exempt PIPs, i.e., those that can be 
created through conventional breeding; (2) Would be subject to 
recordkeeping requirements and documentation for exemption (Unit 
III.D.); and (3) Would at least initially be subject to the EPA 
confirmation process (Unit III.C.3.). By adhering to these 
requirements, EPA can ensure that any future categories of PIPs created 
through genetic engineering from sexually compatible plants will remain 
within the scientific scope that was presented in the proposal, and 
that underlies the current exemptions at 40 CFR 174.26, and that these 
categories would remain subject to the procedural guard rails set in 
place by the eligibility determination process.
    The proposed regulatory text included additional categories that 
are not being finalized under 40 CFR 174.26. To increase clarity, the 
category encompassing ``loss-of-function PIPs'' that was proposed at 40 
CFR 174.26(a)(2)(iv) has been removed and a new, stand alone exemption 
for ``loss-of-function PIPs'' at 40 CFR 174.27 was created in its place 
(Unit III.B.). Proposed 40 CFR 174.26(a)(2)(i) allowed for regulatory 
region modifications so long as the pesticidal substance remained 
unchanged, but relied on proposed 174.26(b) to specify the bounds of 
the expression profile. However, EPA received public comment stating 
that the criterion related to expression profile at proposed 40 CFR 
174.26(b) was unclear (Units IV.C.2. and IV.E.4.b.). In response to 
these comments, 40 CFR 174.26(a)(2) now includes a criterion related to 
inserted regulatory region modifications (i.e., must match 
corresponding polymorphic sequences in a native allele), therefore 
making proposed 40 CFR 174.26(a)(2)(i) redundant. Because proposed 40 
CFR 174.26(a)(2)(i) was removed, proposed 40 CFR 174.26(a)(2)(iii) was 
also removed as it was dependent on proposed 40 CFR 174.26(a)(2)(i). 
Proposed 40 CFR 174.26(a)(2)(ii) is effectively a subset of what is 
possible under codified 40 CFR 174.26(a)(2), and is therefore not 
finalized. Finally, proposed 40 CFR 174.26(b) previously specified 
expression profile bounds, but due to public comment, EPA now includes 
specific criteria related to allowable modifications that could impact 
expression in the subsections of 40 CFR 174.26(a), thereby making 
proposed 40 CFR 174.26(b) unnecessary.
    EPA does not believe that the removal of the proposed categories 
from the final regulatory text at 40 CFR 174.26 reduces the scope of 
PIPs exempted through this rulemaking since proposed 40 CFR 
174.26(a)(2)(iv) is now being finalized as 40 CFR 174.27, proposed 40 
CFR 174.26(a)(2)(ii) represents a subset of what can be accomplished 
under codified 40 CFR 174.26(a)(2), and since proposed 40 CFR 
174.26(a)(2)(i) and proposed 40 CFR 174.26(a)(2)(iii) were deemed 
redundant.
    The final text of 40 CFR 174.26(b) states that the requirements in 
40 CFR 174.21(d) (i.e., the recordkeeping requirements and the 
eligibility determination procedures) must be met in order for the 
exemption to apply. This is minorly revised from the proposed 
regulatory text which stated that the ``exemption does not apply until 
the requirements in subpart E of this part have been met;'' however, 
the recordkeeping requirements are located in subpart D, and therefore 
citing to 40 CFR 174.21(d) is a more streamlined citation.
    In addition to exempting the active ingredient of PIPs created 
through genetic engineering from sexually compatible plants from the 
requirements of FIFRA, EPA is also finalizing the exemption for 
residues of these substances from the requirement of a tolerance under 
the FFDCA at 40 CFR 174.541. The exemption criteria are identical to 
those at 40 CFR 174.26 except that in order to be exempted from the 
requirements of a tolerance, residues of the pesticidal substance must 
also not be present at levels that are injurious or deleterious to 
human health (40 CFR 174.541(b)). The ``injurious or deleterious'' 
language is included in this rule to align with the same criteria found 
in 40 CFR 174.508 for residues of PIPs in sexually compatible plants. 
(https://www.govinfo.gov/content/pkg/FR-2001-07-19/pdf/01-17983.pdf). 
This language was adopted in the 2001 rule in response to comments 
about the potential for naturally occurring compounds to be present in 
foods at hazardous levels and to be more consistent with FDA policy and 
the standard applied to evaluate adulterated food: ``food shall be 
deemed to be adulterated . . . if it bears or contains any poisonous or 
deleterious substance which may render it injurious to health. . . .'' 
21 U.S.C. 342(a)(1). The purpose of this language was to allow 
expeditious removal of the offending food from the market if injurious 
or deleterious levels of a substance were present in food. All of the 
criteria in 174.541 must be met: the conditions in paragraph (a) limit 
the identity of the substance, the condition in paragraph (b) set 
limits on the level of expression in the plant, and the conditions in 
paragraph (c) ensure the application of the exemption is properly 
documented. Regarding the condition in paragraph (b), one example of 
how this might work is if a source plant were to produce a pesticidal 
substance at levels that are injurious or deleterious to human health, 
that PIP would not qualify for exemption if the level of expression in 
the recipient plant matched the injurious or deleterious levels seen in 
the source plant. It is also important to note that EPA considers 
multiple native gene insertions of the same gene to be one PIP (further 
discussed in Unit IV.B.2.), so the criterion related to safe expression 
levels in food plants (40 CFR 174.541(b)) would apply to the overall 
expression level from all inserted gene copies. Developers modifying or 
inserting genes that produce substances with sequence homology to known 
mammalian toxins, toxicants, or allergens should ensure that the levels 
of pesticidal substances are within the ranges of levels generally seen 
in plant varieties currently on the market and known to produce food 
safe for consumption (i.e., ensure that their levels are not injurious 
or deleterious to human health). Such substances expressed above these 
levels would likely trigger additional review during the EPA 
confirmation and may not fit the exemption criteria.
    Additionally, 40 CFR 174.541(c) has been edited to more 
specifically cite to 40 CFR 174.90, rather than the entire subpart E. 
This citation is different from that found at 40 CFR 174.26(b) due to a 
difference in statutes. Specifically, 40 CFR 174.26(b) cites to 40 CFR 
174.21(d), which describes the general qualifications for exemption 
under FIFRA, whereas 40 CFR 174.541 is an exemption from the 
requirement of a tolerance under FFDCA and therefore would not cite to 
exemption qualifications under FIFRA. Because the regulatory text at 40 
CFR 174.26 for the active ingredient of ``PIPs created through genetic 
engineering from a sexually compatible plant'' and the corresponding 
tolerance exemption for residues of these active ingredients at 40 CFR 
174.541 are identical (except for

[[Page 34762]]

the two clauses discussed in this paragraph) all other changes to the 
regulatory text that were discussed for 40 CFR 174.26 in this Unit were 
also applied to 40 CFR 174.541.

B. Exemption of ``Loss-of-Function PIPs''

    This rule exempts ``loss-of-function PIPs'' from all FIFRA 
requirements, except for the adverse effects reporting requirements at 
40 CFR 174.71, the recordkeeping requirements at 174.73 (as specified 
in 40 CFR 174.21(d)), and the eligibility determination process 
outlined in subpart E. The exempt PIPs represent a subcategory of PIPs 
described in the proposed rule (Ref. 2). In this final rule, EPA is 
creating a separate exemption for ``loss-of-function PIPs,'' which 
allows the Agency to create criteria specific to these types of PIPs 
and an accompanying definition for increased clarity. EPA made this 
change in response to comments that indicated the need for greater 
clarity and the broadening of the exemption text related to ``loss-of-
function PIPs'' regarding the identicality of the substance (Unit 
IV.D.2.). As discussed in Unit IV.D.1., the modified genetic material 
of a ``loss-of-function PIP'' constitutes both the pesticidal substance 
and the active ingredient. The language describing the exemption 
appears in 40 CFR 174.27.
1. Associated Definitions
    Because EPA is creating a separate exemption for ``loss-of-function 
PIPs,'' EPA is also codifying a definition associated with the 
exemption in 40 CFR 174.3:
    ``Loss-of-function plant-incorporated protectant'' means a plant-
incorporated protectant in which the genetic material of a native gene 
is modified to result in a pesticidal effect through the reduction or 
elimination of the activity of that gene. For purposes of loss-of-
function plant-incorporated protectants, the active ingredient and 
pesticidal substance are one and the same and are defined as the 
genetic material that has been modified to create the pesticidal trait 
(i.e., modification of the sequence of nucleic acids). Loss-of-function 
plant-incorporated protectants do not include instances where the 
reduction or elimination of the activity of the modified native gene 
results in the intentional increase of activity of another pesticidal 
gene.
    The first sentence of this definition specifies that for a PIP to 
be considered a ``loss-of-function PIP,'' a pesticidal effect must be 
created through the genetic modification of a native gene, which then 
leads to the reduction or elimination of the activity of that native 
gene. The second sentence defines the regulated substance (see Unit 
IV.D.1. for additional discussion). The third sentence explicitly 
excludes the scenario in which a modification of a native gene not only 
leads to the reduction in the expression of that native gene, but 
additionally leads to an increase of activity of another, ``secondary'' 
gene, with that ``secondary'' gene then conferring the pesticidal 
activity (e.g., the altered gene encodes for a repressor whose absence 
does not itself lead to a pesticidal effect but rather the increased 
expression of a second gene that encodes a pesticidal substance). This 
definition is consistent with the description of ``loss-of-function 
PIPs'' in Unit VII.E. of the proposed rule (Ref. 2).
2. Exemption Criteria
    Both the definition at 40 CFR 174.3 and the exemption text at 40 
CFR 174.27 focus on the loss-of-function trait that results from the 
modification (i.e., the reduction or elimination of the activity of the 
modified gene), and do not include requirements related to source 
plants or limit the location within the gene to which modifications are 
allowed to be made (i.e., regulatory region or coding region). 
Specifically, 40 CFR 174.27 specifies two requirements, the first of 
which at 40 CFR 174.27(a) is almost identical in language to the loss-
of-function definition and specifies that the genetic modification must 
result in a ``loss-of-function PIP.'' The type of genetic modification 
to a native gene that results in the loss of activity of that gene is 
not relevant so long as a ``loss-of-function PIP'' is the result of 
that modification. As with the exemptions at 40 CFR 174.26, the second 
requirement at 40 CFR 174.27(b) specifies that the exemption for 
``loss-of-function PIPs'' only goes into effect after the requirements 
for the eligibility determination in 40 CFR 174.21(d) have been met.
    In the proposed rule, ``loss-of-function PIPs'' were a subcategory 
under 40 CFR 174.26 (specifically proposed 40 CFR 174.26(a)(2)(iv)), 
and they were held to the same ``identical substance'' criterion as 
other PIPs described in proposed 40 CFR 174.26. While the EPA does not 
find that it can make an a priori safety determination under FIFRA and 
FFDCA for non-identical pesticidal substances now exempted under 40 CFR 
174.26 (Unit IV.C.1.), it finds that no such restriction is warranted 
for ``loss-of-function PIPs'' under 40 CFR 174.27 (Unit IV.D.2.). This 
conclusion is based on characteristics of ``loss-of-function PIPs,'' 
the common occurrence of pesticidal traits resulting from the loss-of-
function of endogenous genes in conventional breeding, and the 
biological processes that all proteins undergo within plants (Unit 
IV.D.2.).
    The absence of function is a hallmark of ``loss-of-function PIPs,'' 
e.g., loss of the activity of a native gene that would otherwise 
facilitate the susceptibility of that plant to a pathogen. Importantly, 
the criteria and definition state that for a ``loss-of-function PIP,'' 
the native gene modification results in a pesticidal effect from the 
reduction or elimination of the activity of that gene. This indicates a 
direct cause-and-effect relationship between the reduction in the 
expression of a specific native gene and a pesticidal effect. This 
direct cause-and-effect relationship also means that not all 
modifications that lead to a loss-of-function of a gene and that result 
in a pesticidal effect are considered ``loss-of-function PIPs.'' For 
example, this scenario may occur if a modification of a native gene not 
only leads to the reduction in the expression of that native gene, but 
also to an increase of the activity of another, ``secondary'' gene, 
with that ``secondary'' gene then conferring the pesticidal activity 
(e.g., the altered gene encodes for a repressor protein whose absence 
does not itself lead to a pesticidal trait but rather the increased 
expression of a second gene that encodes a pesticidal substance). 
Because in this instance there is no direct cause-and-effect 
relationship between the reduction of the expression of the modified 
native gene and the pesticidal effect, that gene modification and 
resulting ``secondary'' activity would not be considered a ``loss-of-
function PIP'' under 40 CFR 174.27. Further, in the scenario described, 
that gene modification and resulting ``secondary'' activity would only 
be exempt under the new regulations if it meets the criteria outlined 
in 40 CFR 174.26 and from FFDCA if the residues meet the requirements 
under 40 CFR 174.541. For ``loss-of-function PIPs,'' EPA clearly 
indicates the requirement for this direct cause-and-effect relationship 
of native gene modification and the pesticidal effect in the second 
sentence of the ``loss-of-function PIP'' definition.

C. Eligibility Determination Process

    The Agency is finalizing subpart E, which includes provisions 
describing the eligibility determination process and documentation 
required for an exemption of certain PIPs. Specifically, in order for a 
PIP listed under 40 CFR 174.21(d) to be eligible for exemption, an 
exemption eligibility determination must be completed prior to engaging 
in

[[Page 34763]]

FIFRA-regulated activities. EPA agrees with commenters arguing that 
requiring an eligibility determination will provide additional clarity 
to developers of PIP products under certain circumstances and increase 
transparency and public trust in products containing these PIPs (Unit 
IV.E.1.). The primary difference between the proposal and the final 
rule is the restriction of the self-determination option to only 
certain PIPs exempted by this rulemaking. In the proposal, all exempted 
PIPs had the option of self-determination. However, in the final rule, 
only developers of ``loss-of-function PIPs'' (40 CFR 174.27) currently 
have the option to self-determine whether the exemption criteria are 
met. To that end, modifications were made to proposed 40 CFR 174.90, 40 
CFR 174.91, and 40 CFR 174.93 (Units III.C.1., C.2., and C.3.). In 
addition, the titles of these three subsections were minorly revised 
from the proposal for clarity.
    Given the straightforward criteria describing ``loss-of-function 
PIPs'' (i.e., a focus on function rather than source plant or 
underlying sequence), EPA believes it is appropriate for ``loss-of-
function PIPs'' to be eligible for the self-determination option as it 
is unlikely for a developer to accidentally misdetermine exemption 
eligibility of these PIPs. Additionally, the mode of action of ``loss-
of-function PIPs'' (i.e., reduction or elimination of an endogenous 
gene) is fundamentally different from ``PIPs created through genetic 
engineering from a sexually compatible plant'' (e.g., intentional 
production of a pesticidal protein), and as such, further lends itself 
to the availability of a self-determination option. Although ``PIPs 
created through genetic engineering from a sexually compatible plant'' 
are not currently eligible for the self-determination option, EPA 
intends to reconsider this in future rulemakings.
    A separate determination of eligibility of exemption for purposes 
of the FFDCA exemption for a PIP proposed for use in food or feed is 
required only if that determination has not already been submitted 
under FIFRA. This is because the exemption eligibility determination 
process described in 40 CFR 174.21 already requires the applicant to 
certify that the PIP meets the general qualifications for exemption, 
which includes exemption under the FFDCA for PIPs used in food or feed. 
A scenario in which a developer will need an exemption eligibility 
determination specifically for the purposes of FFDCA, but not FIFRA, 
would be when residues of a PIP are in or on food imported into the 
United States, but the PIP is not intended to be sold or distributed 
for pesticidal use (e.g., PIP-containing seed or plant sold for 
planting) in the United States (and thus is not subject to FIFRA 
regulation). Additional discussion on the types of activities that 
warrant an eligibility determination can be found in Unit IV.E.5.
1. Determining Eligibility
    Regarding the process of an exemption eligibility determination 
under 40 CFR 174.90, this provision states at 40 CFR 174.90(a) that, 
depending on the applicable exemption, developers have two, non-
mutually exclusive options to notify EPA that their PIP meets the 
exemption criteria: (1) Seek EPA confirmation that a PIP meets the 
exemption criteria, and (2) Submit a self-determination letter that a 
PIP meets the exemption criteria. For PIPs subject to the eligibility 
determination process, an EPA confirmation is mandatory unless the PIP 
is listed at 40 CFR 174.90(a)(2) as eligible for the self-determination 
option. For PIPs eligible for the self-determination option, an EPA 
confirmation can be sought instead of, in conjunction with, or 
subsequent to the submission of the self-determination letter.
    As stated in Unit III.C., only ``loss-of-function PIPs'' under 40 
CFR 174.27 are currently eligible for the self-determination option and 
no ``PIPs created through genetic engineering from a sexually 
compatible plant'' under 40 CFR 174.26 are currently listed under 40 
CFR 174.90(a)(2). Therefore all ``PIPs created through genetic 
engineering from a sexually compatible plant'' are required to undergo 
an EPA confirmation process. However, EPA intends to reconsider this in 
future rulemakings, and as such, EPA has codified text at 40 CFR 
174.90(a)(2)(ii) to accommodate this possibility.
    The provision explains at 40 CFR 174.90(b) that submissions for a 
request for EPA confirmation or a letter of self-determination must be 
made electronically, which means that they may not be made by mailing 
the information in physical form to the Agency (e.g., sending hard 
copies or data storage devices such as DVD). Specifically, electronic 
submissions are required to be made through EPA's electronic submission 
portal which receives legally acceptable data in a secure manner (see 
Unit IV.E.6. for additional discussion). That system is used, amongst 
other things, for submission of pesticide registration applications, 
and will now additionally accommodate the eligibility determination 
processes associated with the PIPs identified in this rule. The 
electronic submission process will accommodate submissions when the 
final rule is effective, specifically, 60 days after the date of 
publication in the Federal Register. This electronic submission process 
differs from the proposal, which included instructions on how to submit 
a self-determination or confirmation request via physical mail. 
Guidance for electronic submission can be found in Pesticide 
Registration Notice 2011-3 (Ref. 7) or any subsequent revision or 
replacement. The provision at 40 CFR 174.90(c) also explains the 
procedures that must be followed to claim information submitted as 
confidential.
    For PIPs that are eligible for both the self-determination and EPA 
confirmation options, the provision at 40 CFR 174.90(d) further 
explains the relationship between the EPA confirmation processes and a 
letter of self-determination. Specifically, if a developer chooses to 
request EPA confirmation in accordance with 40 CFR 174.93 in 
conjunction with or subsequent to submitting a self-determination 
letter in accordance with 40 CFR 174.91, the exemption is effective 
from the time the company receives confirmation of submission of the 
self-determination letter. The exemption remains effective if EPA 
affirms the developer's determination that the PIP meets the exemption 
criteria and the self-determination is superseded by EPA's written 
confirmation in response to the confirmation request. Alternatively, in 
instances in which no prior self-determination has been provided to the 
Agency in accordance with 40 CFR 174.91, and the developer submits a 
request for confirmation to the Agency, the exemption applies only once 
EPA provides written notice to the developer confirming that the PIP 
meets the criteria for exemption.
    The provision also includes text at 40 CFR 174.90(e) stating that 
EPA reserves the right to assess or revisit at any time after EPA 
issues a confirmation of eligibility or the letter of self-
determination is submitted, whether a PIP meets, or has met, the 
criteria for exemption. If EPA finds or has reason to believe that, at 
any time before or during this review of eligibility for exemption, the 
product is non-compliant with FIFRA or presents an adverse risk to 
human health, the environment, or program integrity, the Agency can 
take immediate steps--including enforcement--to address that non-
compliance or to protect against those adverse risks. This is revised 
from the proposed text to make explicitly clear

[[Page 34764]]

that although EPA will generally notify the submitter in writing of 
EPA's intention to initiate a review of eligibility for exemption, EPA 
may take such action without first informing the submitter of an 
eligibility review if the situation warrants.
    As exempt PIPs are still subject to 40 CFR 174.71, upon learning of 
any adverse effects (i.e., that a person or nontarget organism 
allegedly suffered an adverse effect due to exposure to a PIP), EPA has 
the authority to evaluate whether the PIP still meets the criteria for 
exemption. As described in the preamble of the July 19, 2001, Federal 
Register notice implementing 40 CFR 174.71 (66 FR 37772; July 19, 2001; 
FRL-6057-7) (Ref. 8), reports involving food or feed (i.e., those 
subject to enforcement under FFDCA) would be made to EPA, but EPA will 
share such reports with FDA. EPA and FDA will individually determine 
whether any action, including the possibility of enforcement, is 
necessary to protect the public health or the environment, and if so, 
what constitutes appropriate action based on their respective statutes 
(EPA-FIFRA; FDA-FFDCA). Additional discussion regarding EPA enforcement 
can be found in Unit III.D.7. of the Response to Comments document 
found in the docket associated with this rulemaking.
    The provision outlines instances at 40 CFR 174.90(f) in which an 
exemption determination for a PIP can be extended to other PIPs. A 
determination that a PIP meets the exemption criteria would be required 
for each modified gene and plant species combination (e.g., PIP ``A'' 
in corn and PIP ``A'' in tomato would each require their own 
determination). However, EPA is aware that a plant species can comprise 
multiple varieties and does not intend for the PIP in each variety to 
require its own submission. In order to extend the exemption for a PIP, 
the developer would need to comply with the provisions outlined in 40 
CFR 174.21(d) for the first modification in that plant species and that 
exemption can then be extended in one of two ways. If the exempted PIP 
is moved through conventional breeding, the exemption is extended to 
the subsequent PIP. To extend the exemption of the PIP to subsequent 
genetic engineering events, the PIP must meet exemption-specific 
criteria outlined by EPA. The paragraph in this text was edited from 
the proposed rule to explicitly state that movement of exempt PIPs 
through conventional breeding also results in the extension of 
exemption status of that PIP and to clarify that the subparagraphs 40 
CFR 174.90(f)(1) and 40 CFR 174.90(f)(2) are specific to genetic 
engineering.
    For a ``PIP created through genetic engineering from a sexually 
compatible plant,'' the exemption extends to subsequent engineering of 
that PIP by the submitter into other varieties of that same plant 
species as long as the subsequent PIP produces the identical substance 
as in the exempt PIP and no new modifications were made to the 
regulatory regions. For example, if a developer first modifies an 
existing gene in a tomato variety to create a native allele, this would 
require a determination; however, if the developer subsequently creates 
the same native allele in another tomato variety, the developer would 
not be required to submit a second determination request for the 
additional variety. For a ``loss-of-function PIP,'' an exemption 
extends to subsequent engineering of that PIP by the submitter into 
other varieties of that same plant species as long as the submitter is 
targeting the same native gene to create the ``loss-of-function PIP.'' 
This text is modified from the proposal based on a comment arguing that 
the criteria should focus on the trait phenotype and function (Unit 
IV.E.2.). As described in Unit IV.D.2., ``loss-of-function PIPs'' now 
have their own exemption category with a focus on function rather than 
substance identity, and as such, the extension of the exemption for 
``loss-of-function PIPs'' is now described in 40 CFR 174.90(f)(2) with 
a similar focus.
    Finally, EPA has added a new paragraph (g) to 40 CFR 174.90, which 
explains that a duplicative eligibility submission is not required for 
purposes of 40 CFR 174.541(c), if it is already being submitted for 
purposes of 40 CFR 174.21(d). This provision was not in the proposal, 
but was added for clarification based on public comment (Unit IV.E.5.). 
Related to these comments, EPA is confirming that the Agency is 
requiring a separate eligibility determination to be made through EPA's 
electronic submission portal for residues of those PIPs under 40 CFR 
174.541 that are imported into the United States and that are used for 
food or feed if the developer has not already obtained an exemption 
under 40 CFR 174.541. This submission includes an acknowledgement that 
the developer is only submitting an exemption eligibility determination 
for the purposes of FFDCA but not FIFRA, and therefore it is not 
permissible for the PIP to be sold or distributed for pesticidal use 
(e.g., PIP-containing seed or plant sold for planting) in the United 
States. As discussed in the preamble of the proposed rule, a separate 
submission of the eligibility determination of the FFDCA exemption for 
a PIP proposed for use in food or feed is required only if it has not 
already been submitted under FIFRA.
2. Process for a ``Letter of Self-Determination'' for a PIP To Qualify 
for an Exemption
    This rule finalizes a new provision in subpart E, 40 CFR 174.91, 
entitled ``Submitting a letter of self-determination'' The provision 
describes the requirements and process of notifying EPA that the 
developer has determined (or ``self-determined'') that a PIP qualifies 
for exemption.
    The provision at 40 CFR 174.91 explains that a developer must 
submit the letter of self-determination prior to engaging in activities 
that would be subject to FIFRA for the proposed PIP (e.g., distribution 
and sale of the PIP at issue). As specified in 40 CFR 174.90(b), self-
determination letters must be submitted electronically. If a developer 
does not have an EPA company number, they will be required to obtain 
one in order to be able to submit a self-determination letter. Self-
determination letters will not be submitted under FIFRA section 33 and 
will not be subject to application fees under the Pesticide 
Registration Improvement Extension Act of 2022 (PRIA 5). The exemption 
does not apply until EPA confirms receipt of the self-determination, 
but since the submission of the self-determination letter will be made 
electronically, the receipt confirmation by the Agency occurs 
automatically upon submission and is considered equivalent to written 
confirmation of receipt.
    The provision at 40 CFR 174.91(b) includes information on the 
required contents of the self-determination letter. This includes a 
statement certifying the developer's determination of exemption 
eligibility, the identity of the recipient plant, a unique gene 
identifier for the native gene, the trait type (e.g., insect 
resistance), and information on the applicable exemption. The gene 
identifier is for the native gene (not necessarily the exact sequence 
of the PIP) and must be from databases curated by the National Center 
for Biotechnology Information (NCBI), which is part of the National 
Library of Medicine of the National Institutes of Health (NLM) at the 
National Institutes of Health (NIH). These databases are available free 
of charge to scientists globally and will ensure availability of the 
gene information to EPA and a means to standardize that information. 
Based on public comment (Unit IV.E.3.), this provision was clarified to 
explicitly request the identity of the recipient plant, an identifier 
for the native gene,

[[Page 34765]]

and the trait type, rather than the name of the PIP, which may or may 
not have included such information. Additionally, rather than listing 
PIP categories eligible for self-determination under 40 CFR 
174.91(b)(2) as had been proposed, the provision now cites to the list 
under 40 CFR 174.90(a)(2). Lastly, EPA streamlined the regulatory text 
by merging 40 CFR 174.91(b)(4) with 40 CFR 174.91(b)(3) and removing 
the text of the certification statement from the provisions. The 
statement is captured in the electronic submission portal and thus 
listing it in the regulatory text was deemed redundant.
    EPA notes that the developer is responsible at all times for 
ensuring the self-determination is accurate and if at any time EPA 
determines that a self-determination was fraudulently or incorrectly 
made, or is no longer accurate due to the availability of new 
information that was not available at the time the self-determination 
was made, EPA will notify FDA of this new information, and the Agencies 
can take action to protect the environment and public health, 
respectively. This includes the possibility of enforcement under FIFRA 
or FFDCA.
3. Process To Obtain an EPA Confirmation That a PIP Qualifies for 
Exemption
    This rule establishes a new provision in subpart E entitled 
``Requesting EPA confirmation'' (40 CFR 174.93), which describes the 
process through which a developer may seek confirmation from EPA as to 
whether a PIP meets the criteria for exemption codified in 40 CFR 
174.21. A developer must submit information as outlined in 40 CFR 
174.91 along with specific supporting documentation. For example, the 
information required to support the request for a ``PIP created through 
genetic engineering from a sexually compatible plant'' is described in 
40 CFR 174.95 and discussed in Unit III.C.4.a.
    In addition, the provision at 40 CFR 174.93 explains that upon 
receipt of the request, EPA will review the submission and determine 
whether the PIP meets all necessary criteria to be exempt under 40 CFR 
174.21. The Agency will notify the submitter in writing of its 
determination. The exemption goes into effect only once the developer 
receives EPA's confirmation in writing, unless a self-determination 
letter was previously submitted. As discussed in Unit III.C.1., EPA 
reserves the right to reassess whether a PIP meets the criteria for 
exemption should the Agency learn of relevant information subsequent to 
confirming its eligibility to be exempt under 40 CFR 174.21.
    Requests for EPA confirmation are to be submitted using the 
submission category (M009) and associated fee structure for a Non-FIFRA 
Regulated Determination under FIFRA section 33 (PRIA). The logistics of 
the submission for a request and EPA review times may change in the 
future if PRIA changes or a different structure for submissions is 
adopted.
4. Documentation for an Exemption
a. PIPs Created Through Genetic Engineering From Sexually Compatible 
Plants
    The rule finalizes the documentation needed for an exemption for 
``PIPs created through genetic engineering from a sexually compatible 
plant.'' There are four main information elements associated with the 
required documentation, which capture the: (1) Biology of the plant; 
(2) Description of how the trait was engineered into the plant; (3) 
Molecular characterization of the PIP; and (4) Information on the 
history of safe use for those PIPs that are either known mammalian 
toxins or toxicants or that are from a source plant that is a wild 
relative of the recipient plant. Collectively, this information allows 
EPA to ensure that a PIP meets the exemption criteria at 40 CFR 174.26 
and 40 CFR 174.541.
    The first element (40 CFR 174.95(a)) requires information on the 
biology of the plant and has two components: (1) The identity of the 
recipient plant, including genus and species; and, if the PIP was 
derived from another plant species, the identity of the source plant, 
including genus and species; and (2) Information to support that the 
recipient plant and the source plant are sexually compatible. The 
regulatory text regarding sexual compatibility was minorly revised from 
proposed ``if the plant-incorporated protectant was derived from 
another plant species'' to ``if the plant-incorporated protectant was 
derived from a plant species other than the recipient plant species'' 
to more directly articulate that this information is only needed if the 
source and recipient plant are taxonomically classified as belonging to 
different plant species. As stated in the preamble of the proposed rule 
(Unit VI.C.4.), to meet this requirement a developer may provide a 
peer-reviewed literature rationale (e.g., breeding guides, journal 
articles) instead of generating empirical data to demonstrate that the 
two plant species are sexually compatible. Therefore, for clarity based 
on public comment (Unit IV.E.4.a.), the regulatory text regarding 
sexual compatibility was further modified to replace ``demonstrate'' 
with ``information to support.''
    The second element (40 CFR 174.95(b)) captures information on the 
pesticidal trait and how it was engineered into the plant. EPA 
anticipates that this element can be addressed through a narrative 
description of the intended pesticidal function of the PIP and 
information on the techniques used to make the genetic modification in 
the recipient plant (e.g., the molecular tools used, transformation 
method). The text was revised from the proposal to also require 
information on the steps that were taken to ensure that no engineering 
components (i.e., PIP inert ingredients) are expected to remain in the 
final plant product. Engineering components include, but are not 
limited to, those associated with the genetic engineering of the plant 
itself (e.g., Cas protein) and selectable markers that, in the early 
steps of PIP development, aid in the selection of plant transformants 
that contain the desired traits (e.g., herbicide resistant markers). 
Unless the engineering components themselves meet the requirements at 
40 CFR 174.705, they would not be exempt inert ingredients. Thus, by 
requiring this information, EPA will be able to ensure that no 
unapproved inert ingredients are expected to remain in the final plant 
product. Similarly, based on public comment (Unit IV.A.2.), EPA has 
also included a requirement that the developer describe the measures 
taken to maximize the likelihood that the modification to the recipient 
plant is limited to the intended modification, including ensuring off-
target mutations were minimized (e.g., through the use of in silico 
techniques in guide RNA development). This could be information on the 
specificity of the endonuclease in the recipient plant species and the 
use of predictive in silico tools that can identify other potential 
target sites. As discussed in the preamble of the proposed rule (Unit 
V.A.), by using the definition of a ``gene'' the Agency restricts any 
genetic modifications made through biotechnology that would fall under 
the exemption to modifications to the gene itself. Thus, by requiring 
this information, EPA can determine that this is true.
    The third element (40 CFR 174.95(c)) requires information on the 
molecular identity of the PIP. Specifically, EPA is requiring the 
sequence of the PIP in the recipient plant and its comparator. This was 
revised per public comment to clarify the required sequence 
information, which is based on the

[[Page 34766]]

relevant comparator and the type of pesticidal substance (Unit 
IV.E.4.a.). For example, for native gene insertions the comparator is 
the sequence of the PIP in the source plant, whereas for native genes 
that are modified to match corresponding polymorphic site(s), the 
relevant comparators are the sequence of the PIP in the source plant, 
the modified recipient plant, and the original native gene in the 
unmodified recipient plant. What determines the type of sequence 
information that must be provided is the molecular composition of the 
pesticidal substance. Nucleic acid sequences must be provided for both 
native gene insertions and for genes modified to match a corresponding 
polymorphic site. In addition, if the pesticidal substance is 
proteinaceous, an amino acid sequence must also be provided. In 
addition to basic sequence information, if a native allele has been 
modified according to 40 CFR 174.26(a)(2), then documentation is also 
required that identifies the modified polymorphic sites within the 
relevant sequences.
    To provide more clarity in response to several comments that were 
received on the proposal (Unit IV.E.4.b.), EPA has removed the 
requirement to provide information on the expression profile for those 
PIPs where the regulatory region has been modified. In the final rule, 
EPA was able to remove the requirement to provide information on the 
expression profile because the Agency now includes at 40 CFR 174.26(a) 
specific criteria related to allowable modifications that could impact 
expression, thereby restricting expression to what is found in the 
sexually compatible plant population.
    The fourth element (40 CFR 174.95(d)) captures the requirement from 
proposed 40 CFR 174.95(b) for pesticidal substances that are known 
allergens or mammalian toxins/toxicants. For these substances, a 
description of how conventional breeding practices are being used to 
ensure they do not exceed human dietary safety levels in the recipient 
food plant must be provided. EPA revised this from the proposed text to 
specify ``human dietary safety levels'' rather than ``safe levels'' for 
clarity. EPA also added a clarifying parenthetical, ``ensure residues 
of pesticidal substance are not present in food at levels that are 
injurious or deleterious and are within the ranges of levels generally 
seen in plant varieties currently on the market and/or known to produce 
food safe for consumption,'' to further define what is meant by ``human 
dietary safety levels.'' EPA is aware that the conventional breeding 
process is generally comprised of three stages: trait mapping, trait 
introgression, and field testing (Ref. 9). Through genetic engineering, 
the second stage, trait introgression, can occur more quickly and more 
precisely (i.e., insert only the trait of interest without linkage drag 
of undesirable traits). However, trait mapping (requires knowledge of 
plant genetics and biology, likely includes an understanding of any 
naturally occuring plant toxins) and field testing (evaluates traits 
related to agronomic parameters, consumer preferences, allergens/
toxins/nutrition) are expected to still occur under their normal 
timeframes. The second component of this section is specific to those 
PIPs that are from a source plant that is a wild relative, i.e., a non-
domesticated relative. 40 CFR 174.95(d)(2) is new and was added as a 
result of comments that the Agency received on the proposed rule (Unit 
IV.E.4.a.). For PIPs from wild relatives, a rationale as to why they do 
not pose a hazard to humans or the environment must be submitted. 
Several examples of the type of information that can be used to address 
this requirement are provided in the regulatory text itself.
    Information described under elements one through four will inform 
whether the PIP meets criteria (a) and (b) of the FIFRA exemption and 
criteria (a) and (b) of the FFDCA exemption for the requirement of a 
tolerance for residues of PIPs.
b. Loss-of-Function PIPs
    This rule also finalizes the documentation needed for an exemption 
for ``loss-of-function PIPs.'' As discussed in Unit III.B., ``loss-of-
function PIPs'' have now been removed as a subcategory from 40 CFR 
174.26 and an exemption specific to ``loss-of-function PIPs'' has been 
created at 40 CFR 174.27. Consequently, establishment of documentation 
requirements for this PIP category were necessary (40 CFR 174.96). As 
the ``loss-of-function PIPs'' exemption is focused on phenotype rather 
than specific underlying nucleic acid sequences, the documentation 
associated with the exemption is similarly focused on the trait. To 
this end, the identity of the modified plant (i.e., genus and species) 
and a description of the pesticidal trait is required (40 CFR 
174.96(a)). Along with the description of the pesticidal trait, a 
description of how the trait was engineered is also required (40 CFR 
174.96(b)). This includes a description of the steps that were taken to 
ensure that no engineering components (e.g., Cas proteins) are expected 
to remain in the plant and measures taken to maximize the likelihood 
that the modification to the recipient plant is limited to the intended 
modification, including ensuring off-target mutations were minimized 
(e.g., through the use of in silico techniques in guide RNA 
development). This information allows the EPA to ensure the criteria 
for exemption are met (e.g., no non-exempt inert ingredients remain in 
the final plant).

D. Recordkeeping Requirements for PIPs Exempt by This Rulemaking

    At 40 CFR 174.73, subpart D, EPA is codifying a requirement under 
FIFRA section 3(a) that any person who is required to submit 
documentation for the eligibility determination of a PIP under 40 CFR 
174.21(d), must maintain documentation of either the request for EPA 
confirmation or the letter of self-determination (or both, if 
applicable) along with all supporting documentation for the specific 
exemption as specified in subpart E. These documents must be maintained 
for five years starting with the effective date of the exemption. This 
text is minorly revised from the proposed text for clarity.

E. Clarification of General Qualifications for Exemption

    This rule finalizes edits to the ``General Qualifications for 
Exemptions'' provisions at 40 CFR 174.21 to clarify the applicability 
of this framework to other PIP exemptions. For paragraph (a), this 
revision simply clarifies that this paragraph is specific to the active 
ingredient of the PIP, rather than the PIP as a whole. This is because 
the definition of a PIP under 40 CFR 174.3 also includes ``any inert 
ingredient,'' and inert ingredients are not exempt under subpart B but 
rather subpart X. In the proposed rule, EPA used the phrase 
``pesticidal substance'' in its proposed revisions to 40 CFR 174.21(a), 
while in the final rule, the Agency uses the phrase ``active 
ingredient.'' The active ingredient definition at 40 CFR 174.3 includes 
both the genetic material and any pesticidal substance produced (e.g., 
a protein). Exemption criteria related to both the genetic material and 
the pesticidal substance are specified in exemptions under subpart B. 
As such, the titles for the exemptions in subpart B are similarly 
codified to specify ``active ingredient.''
    Paragraph (b) is revised to refer to subpart W, rather than the 
specific sections and is also revised to specify that the tolerance 
exemptions apply to the residues of the active ingredient, rather than 
the PIP as a whole for the same rationale as outlined for the edit

[[Page 34767]]

to 40 CFR 174.21(a). It should be noted that although paragraph (b) 
specifies active ingredient, there are separate tolerance exemptions 
specific to both the residues of the pesticidal substance (e.g., 40 CFR 
174.541) and the genetic material (i.e., 40 CFR 174.507) under subpart 
W.
    Paragraph (c) is revised to refer to subpart X, rather than the 
specific section of 40 CFR 174.705.
    EPA is also finalizing a new paragraph (d) in section 40 CFR 174.21 
to accommodate the exemption eligibility determination process (Unit 
III.C.) and the recordkeeping requirements (Unit III.D.). This 
paragraph specifies that for PIPs listed in the subsequent 
subparagraphs, the exemption is contingent upon compliance with 
recordkeeping requirements and the eligibility determination process. 
The addition of paragraph (d) does not impact the exemption under 
section 40 CFR 174.25 for PIPs from sexually compatible plants through 
conventional breeding as this exemption is not identified in paragraph 
(d). EPA made two revisions to 40 CFR 174.21(d) since proposal of the 
rule. First, the Agency added a clarification that 40 CFR 174.73 is 
implemented ``per sections 8 and 9 of FIFRA (U.S.C. 136f and 136g).'' 
Those sections of FIFRA specify EPA's inspection authority and impose 
recordkeeping requirements and they still apply to the PIPs exempted 
under this rule. Secondly, ``[Reserved]'' was moved to 40 CFR 
174.21(d)(3) and replaced in its proposed position at 40 CFR 
174.21(d)(2) with ``Loss-of-function plant-incorporated protectants,'' 
to accommodate the newly created exemption for these types of PIPs at 
40 CFR 174.27.

F. Clarification of the Exemption for Sexually Compatible PIPs

    The rule finalizes clarifications of the relationship between the 
newly exempted ``PIPs created through genetic engineering from a 
sexually compatible plant'' and ``loss-of-function PIPs'' with the 
previous FIFRA and FFDCA exemptions related to conventionally bred 
plants (i.e., 40 CFR 174.25 and 40 CFR 174.508). EPA inserted ``created 
through conventional breeding'' at the end of each section title, and 
inserted an additional criterion into 40 CFR 174.25 and 40 CFR 174.508, 
stating that the genetic material is transferred only through 
conventional breeding. The exemptions at 40 CFR 174.25 and 40 CFR 
174.508 have always meant ``only through conventional breeding,'' but 
this clarification is necessary given the amended definition for 
``sexually compatible.''

G. Inert Ingredient Exemption Includes Genetic Engineering

    While EPA revised 40 CFR 174.25 and 40 CFR 174.508 to include a 
criterion specifying that the genetic material is transferred from the 
source plant to the recipient plant only through conventional breeding, 
a parallel revision was not proposed or finalized at 40 CFR 174.705.
    The amended definition for ``sexually compatible'' states that 
``plants must be capable of forming a viable zygote through the union 
of two gametes through conventional breeding'' (emphasis added), which 
differs from the definition promulgated in 2001 that specified that ``a 
viable zygote is formed only through the union of two gametes through 
conventional breeding'' (emphasis added). The amendment of the 
``sexually compatible'' definition therefore removes the criterion that 
the gamete formation may only occur through conventional breeding, 
which would otherwise preclude the use of genetic engineering to create 
PIPs that are exempt even if those PIPs are moved between sexually 
compatible plants. Because EPA is not adding an additional conventional 
breeding criterion to 40 CFR 174.705, like it is for 40 CFR 174.25 and 
40 CFR 174.508, the inert ingredient exemption at 40 CFR 174.705 is no 
longer bound by conventional breeding and therefore allows for the 
exemption of inert ingredients that are initiated through 
biotechnology, so long as they still meet the existing criteria of that 
section.

IV. Discussion of Public Comments and the Agency's Responses

    EPA received a total of 8,120 comments on the proposed rule. Of 
those, 28 were unique and one of those unique comments was supported by 
8,093 co-signers. Comments were received from private citizens, 
industry, academia, professional and trade associations, State 
regulatory associations, and public interest groups. Of the 28 unique 
comments, twenty-three were generally supportive of an exemption for 
PIPs created through biotechnology, while three comments, one of which 
included the mass mailer, were opposed. An additional two respondents 
commented on specific aspects of the rule while remaining silent as to 
their overall position on its promulgation.
    In this unit, EPA provides a summary of the major issues raised by 
commenters and EPA's responses, as well as summaries of public comments 
that prompted changes to the proposed requirements for the final rule. 
All public comments and EPA's responses, including those that do not 
raise significant issues or substantially change the proposed 
requirements, are included in Response to Comments document (Ref. 1).

A. Definitions and Titles

1. Relationship Between ``Conventional Breeding'' and the Terms 
``Native'' and ``Never Derived''
    In the proposed rule, EPA sought comment on whether the intent 
behind the use of the terms ``native'' and ``never derived'' is clear 
or whether alternative phrasing should be used instead. Most of the 
commenters that responded to this request stated that EPA's intent was 
clear but had suggestions on edits to the definitions of ``native 
gene'' and ``native allele.'' A concern raised by several of the 
commenters was that alleles that emerged from the use of common 
conventional breeding techniques, such as induced mutagenesis, may be 
unintentionally excluded from the definition of ``native allele.'' 
Thus, some commenters suggested explicitly including the use of induced 
mutagenesis, embryo rescue, and other conventional breeding techniques 
in the 40 CFR 174.3 definitions for ``native allele,'' ``native gene,'' 
``sexually compatible,'' or ``conventional breeding.'' Another 
commenter provided an alternative and suggested to focus on the 
exclusion of transgenes from the native gene definition more 
explicitly. EPA agreed with the suggestion to focus on the exclusion of 
transgenes and revised the definition accordingly (Unit III.A.1.). As 
stated in the proposal, the Agency does not mean to imply that using 
the term ``native'' would exclude genes originated through conventional 
breeding techniques like mutagenesis. Native genes comprising the gene 
pool of sexually compatible plant populations have been developed 
through the processes of mutation, selection, and genetic exchange. 
Mutations in any part of a gene can occur naturally or may be induced 
including through chemical mutagenesis used by plant breeders to create 
new varieties. Alleles found in sexually compatible plants that may 
have been created through conventional breeding would be included in 
the definition of ``native allele'' and ``native gene.'' Additionally, 
as the requirement does not specify an allele frequency that must be 
met to qualify as a native allele, identifying one individual with a 
particular allele is sufficient to claim an allele as a ``native 
allele.'' EPA also notes that there is no time component of the 
requirement, and so use of a

[[Page 34768]]

native allele identified in a plant from the 1950s, for example, is 
permissible so long as that plant species is a species known to be 
sexually compatible with the recipient plant.
    Regarding requests to explicitly list conventional breeding 
techniques like mutagenesis in one of the definitions, EPA does not 
find this to be necessary, and listing specific conventional breeding 
techniques may only serve to further cause confusion. EPA finds that 
the techniques listed in the conventional breeding definition (e.g., 
bridging crosses and wide crosses) focus on the merging of genetic 
material from different organisms. Therefore, specific conventional 
breeding techniques, such as induced mutagenesis, are not explicitly 
included in the ``conventional breeding'' definition because they are 
not relevant techniques to the merging of genetic material between 
organisms.
2. Definition of ``Genetic Engineering''
    Two commenters requested that the term ``biotechnology'' be 
defined. As the regulations have a definition for ``conventional 
breeding'' under 40 CFR 174.3, which forms the basis for the exemption 
under 40 CFR 174.25, EPA agrees that it would be prudent to similarly 
provide a definition to inform the exemption under 40 CFR 174.26. Given 
that USDA's recent revisions to 7 CFR 340 use the phrase ``genetic 
engineering,'' EPA chose to define ``genetic engineering'' rather than 
``biotechnology,'' to provide consistency across the Coordinated 
Framework (Ref. 3). EPA thusly updated the term used in the exemption 
title to be ``genetic engineering.'' EPA used ``genetic engineering'' 
and ``biotechnology'' synonymously in its proposed rule as evidenced by 
Unit VI.A.3.g. titled ``Are there any considerations associated with 
newer biotechnology techniques?,'' where EPA discussed genetic 
engineering techniques like clustered regularly interspaced short 
palindromic repeats (CRISPR), zinc-finger nucleases, transcription 
activator-like effector nucleases, and oligonucleotide-directed 
mutagenesis.
    EPA also received comments requesting the Agency limit the 
definition of ``genetic engineering'' and therefore the exemptions at 
40 CFR 174.26 and 40 CFR 174.27 to high precision techniques such as 
CRISPR. The Agency has chosen to adopt a broader definition of 
``genetic engineering,'' which is more consistent with the dictionary 
definition of the term. Although the exemptions at 40 CFR 174.26 and 40 
CFR 174.27 are not restricted to specific genetic engineering 
techniques, the exemption criteria in the provisions themselves 
inherently limit the types of techniques which are likely to be used. 
For example, it is unlikely for a developer to be able to make the 
modifications described in 40 CFR 174.26(a)(2)(i) or 40 CFR 
174.26(a)(2)(ii) using techniques other than high precision 
technologies.
    Commenters also pointed out that such high precision techniques can 
be used to limit potential off-target effects from genetic engineering. 
EPA agrees with the commenters that existing gene editing technologies 
can be used in a manner to limit off-target effects (e.g., through the 
use of in silico analyses in guide RNA development), and EPA notes that 
it is expected that the majority of developers already use these types 
of techniques (Ref. 10). Rather than explicitly limiting the exemption 
to specific gene modifying techniques, such as CRISPR, the Agency has 
added an item in the documentation required for developers in 40 CFR 
174.95 to describe the measures taken to maximize the likelihood that 
the modification to the recipient plant is limited to the intended 
modification (Unit III.C.4.a.). As noted, it is anticipated that 
developers are already utilizing basic measures to reduce off-target 
effects, and as such, EPA does not anticipate that this requirement for 
a description would be unduly burdensome.
3. Title of the Exemption, Name of Exempted PIPs
    EPA received comments related to various aspects of the name EPA 
chose for PIPs proposed for exemption under 40 CFR 174.26. One 
commenter requested that EPA move the clause ``created through 
biotechnology'' to directly follow ``PIP.'' The concern was that the 
original phrasing of ``PIPs based on sexually compatible plants created 
through biotechnology'' may suggest that the plant has been modified to 
be sexually compatible, rather than the intended requirement that the 
resulting PIP be based on a PIP from a sexually compatible plant. EPA 
agreed with this comment and reordered the clauses as suggested for 
clarity.

B. Clarification on Allowable Modifications

1. Noncoding, Nonexpressed
    EPA received several comments requesting clarification as to 
whether the presence of ``noncoding, nonexpressed nucleotide 
sequences'' would affect the exemption status of a PIP at 40 CFR 
174.26(a). Commenters argued that because noncoding, nonexpressed 
sequences are currently excluded from the definition of ``genetic 
material necessary for the production'' at 40 CFR 174.3, their presence 
in the recipient plant should not affect the exemption status of a PIP 
that otherwise meets the exemption criteria.
    ``Noncoding, nonexpressed nucleotide sequences'' are defined at 40 
CFR 174.3, in part as ``nucleotide sequences that are not transcribed 
and are not involved in gene expression.'' One such example are the 
left and right border sequences that flank the genetic material that is 
inserted into the plant genome when using Agrobacterium-mediated 
transformation. These sequences facilitate the integration of the 
genetic cargo into the plant genome and will remain in the recipient 
plant together with the genetic material that the developer wishes to 
express to create the pesticidal trait. Other examples of ``noncoding, 
nonexpressed nucleotide sequences'' are linker sequences and 
restriction enzyme recognition sites.
    As discussed in the preamble of the proposed rule, ``EPA expects 
that any ingredients intentionally added during the development of 
``PIPs created through genetic engineering from a sexually compatible 
plant'' that are specific to the production of the active ingredient 
(e.g., guide RNA, DNA nuclease) and that could function as an inert 
ingredient would either be transiently transformed or would be removed 
(e.g., through segregation of the trait) during the breeding process 
and that if these ingredients have not been removed from the final 
product the product would not meet the criteria proposed under the new 
40 CFR 174.26 and would not qualify for the new exemptions.'' Like the 
inert ingredients cited in this quote, noncoding, nonexpressed 
sequences are intentionally added during the development of the PIP to 
facilitate the integration of the genetic cargo. Thus, EPA finds that 
if these sequences are not removed from the final product, i.e., the 
recipient plant, they similarly do not meet the criteria for exemption 
under 40 CFR 174.26 and 40 CFR 174.27. In this way, the PIPs exempted 
under this rulemaking remain indistinguishable from those created 
through conventional breeding.
2. Editing or Insertion of Multiple PIPs in a Single Event
    EPA received requests to clarify whether modifications to multiple 
genes within a single recipient plant would qualify for the exemptions 
at 40 CFR 174.26. The exemptions at 40 CFR 174.26 and 40 CFR 174.27 do 
not limit the number of PIPs that can be created in a single recipient 
plant. Therefore,

[[Page 34769]]

changes to multiple genes in a single recipient plant are allowed, so 
long as each resulting PIP individually meets the exemption criteria. 
In these instances, the M009 PRIA fee for an EPA determination applies 
to each individual PIP, meaning that if one plant contains multiple 
unique PIPs, the M009 PRIA fee would apply multiple times (e.g., the 
M009 PRIA fee is applied three times for the creation of three unique 
PIPs in a single recipient plant). The exception is a scenario in which 
the same gene is modified or inserted multiple times across the genome. 
For example, it may be necessary to modify several homologous genes of 
a native gene in a recipient plant to create a single PIP (i.e., to 
create a loss-of-function PIP where the trait requires all homologous 
genes to be modified). Conversely, a developer may wish to insert 
multiple copies of the same native gene. In the instance of modifying/
inserting the same gene multiple times across the genome, the M009 fee 
is only applied once, as the application contains only one PIP.

C. PIPs Created Through Genetic Engineering From a Sexually Compatible 
Plant

1. Identical Substance Criterion
    EPA received several comments on the ``identical substance'' 
criteria stating, amongst other things, that modifications that result 
in non-identical substances may not result in a change in risk profile 
and that the requirement for the production of an identical substance 
is not consistent with the requirements for PIPs from sexually 
compatible plants that are moved through conventional breeding. In 
response, EPA has edited the exemption category related to 
modifications in an existing native gene at 40 CFR 174.26(a)(2) to 
incorporate the use of polymorphic regions (Unit III.A.2.).
    The exemption category at 40 CFR 174.26(a)(2) does not require the 
production of an identical substance, while still staying within the 
scope of what could be achieved through conventional breeding and thus 
within the scope of the proposed rulemaking. The exemption criterion at 
40 CFR 174.26(a)(2) now allows for modifications of the existing native 
gene using a single source plant as a template to match corresponding 
polymorphic sequence(s) in a native allele of that gene. Polymorphisms 
are variants of a gene sequence that are shared between native alleles. 
These genetic variations may be composed of single nucleotides (i.e., 
SNPs) or larger DNA segments and they are found at the same locus 
within the genetic sequence of two or more native alleles (Ref. 11). In 
some cases, enhanced pesticidal properties of a gene product can be 
attributed to one or more of these genetic variations within a native 
gene. 40 CFR 174.26(a)(2) allows developers to utilize their knowledge 
of specific polymorphisms in native alleles to make changes to the 
native gene in their recipient plant. While this category does not 
require the entire substance to be identical to a substance found in 
the sexually compatible population of the recipient plant, it does 
require the individual polymorphism(s) to have been identified. It is 
also important to note that this category requires the use of a single 
source plant as a template, meaning it is not allowed to combine 
polymorphisms from multiple native alleles in a single PIP. By 
requiring the polymorphic sequences to be identical and the use of a 
single source plant as a template, this separate exemption category 
allows the Agency to capture more of the possible genetic variation 
that can occur in plants, while staying within the bounds of what could 
have been achieved through conventional breeding.
2. Expression Profile Criterion
    EPA proposed at 40 CFR 174.26(b) a criterion that was intended to 
ensure that the expression profile of exempted PIPs falls within that 
which is found in the sexually compatible population. Limiting 
expression profiles of exempted PIPs in this way is a key limitation to 
prevent novel environmental and dietary exposures. However, commenters 
expressed concern over the feasibility to generate the information 
required to demonstrate eligibility for exemption and had several 
questions on how these requirements could be met (Unit IV.E.4.b.). 
Additionally, the Agency received requests to clarify whether the 
criteria that the pesticidal substance may not be expressed at higher 
levels, in different tissues, or at different developmental stages, 
would apply simultaneously or independently. Commenters also requested 
clarification on the identity of the appropriate comparator for the 
expression profile criteria at 40 CFR 174.26(b). These comments 
prompted the Agency to reevaluate the text proposed at 40 CFR 
174.26(b).
    Given the number of comments received surrounding the expression 
criteria, and that limiting expression profiles of exempted PIPs is a 
key limitation to prevent novel environmental and dietary exposures, 
EPA is not codifying proposed 40 CFR 174.26(b) and is instead 
finalizing specific criteria at codified 40 CFR 174.26(a) related to 
the types of permissible modifications that may impact expression. EPA 
now requires that regulatory regions inserted as part of a native gene 
per codified 40 CFR 174.26(a)(1), be identical to those found in the 
native gene in the source plant. The exemption category at 40 CFR 
174.26(a)(2) specifies that modifications to an existing native gene, 
which includes regulatory and coding regions, must match corresponding 
polymorphic sequence(s) in a native allele. By requiring that inserted 
regulatory regions match those found in the native gene in the source 
plant and that modified regulatory regions match polymorphic sequences 
found in a native allele, EPA can ensure that the expression profile of 
PIPs exempted under 40 CFR 174.26 will stay within the bounds of what 
could be obtained through conventional breeding. Furthermore, this 
criterion coupled with the information on the history of safe use (40 
CFR 174.95(d)) allows EPA to ensure that the expression profile of PIPs 
exempt from the requirement of a tolerance under 40 CFR 174.541 meet 
the requirement that expression be at levels that are not injurious or 
deleterious to human health.

D. Loss-of-Function PIPs

1. How are Loss-of-Function Traits Regulated Under FIFRA?
    EPA received a number of comments questioning whether loss-of-
function traits conferring pesticidal effects are considered pesticides 
under FIFRA. As stated in the preamble of the proposed rule (Ref. 2), 
EPA considers the modification of existing native genes in a plant that 
elicit a loss-of-function trait conferring a pesticidal effect, i.e., 
``loss-of-function PIPs,'' to be a pesticide. In the case of ``loss-of-
function PIPs,'' the genetic material of the plant has been altered to 
reduce or eliminate the activity of a gene that would otherwise 
facilitate the susceptibility of that plant to a pathogen; therefore, 
the reduction or elimination of that activity has a mitigating or 
pesticidal effect.
    FIFRA defines a ``pesticide,'' in relevant part, as ``any substance 
or mixture of substances intended for preventing, destroying, 
repelling, or mitigating any pest.'' FIFRA section 2(u), 7 U.S.C. 
136(u). For ``loss-of-function PIPs'' (now exempted under 40 CFR 
174.27), the modified genetic material, e.g., the modified gene or the 
genetic material surrounding an excised gene, is the pesticidal 
substance, since that material operates in the plant to mitigate the 
pest. Further, the modified

[[Page 34770]]

genetic material has been modified with the intent to mitigate the 
pest. Therefore, any plant containing the loss of function trait sold 
or distributed with pesticidal claims would meet the statutory 
definition of a pesticide.
    Under EPA's regulations, a substance is considered to be intended 
for a pesticidal purpose if, among other things, the person who 
distributes or sells the substance as a pesticide product claims, 
states, or implies that the substance can or should be used as a 
pesticide; the substance has no significant commercially valuable use 
other than use for pesticidal purpose; or a person sells or distributes 
a product with actual or constructive knowledge that the product will 
be used, or is intended to be used, for a pesticidal purpose. See 40 
CFR 152.15. Therefore, products carrying a pesticidal claim, such as 
stating that the plant variety resists disease, indicate clear 
pesticidal intent. Further, even if such claims were not made, if the 
seller or distributor knew that the loss of function trait was 
contained in the plant, the substance would still be considered to be 
intended for a pesticidal purpose. Likewise, even for loss-of-function 
PIPs that result in the complete elimination of activity from the 
modified genetic material, the intentional modification of the plant's 
genetic material to result in a pesticidal effect indicates that the 
developer has actual or constructive knowledge that the substance will 
be used, or is intended to be used, for a pesticidal purpose and that 
there is not a significant commercially valuable use other than for a 
pesticidal purpose. The result is that ``loss-of-function PIPs'' are 
subject to regulation under FIFRA. This Final Rule exempts ``loss-of-
function PIPs'' that meet the criteria under 40 CFR 174.27 from certain 
regulation under FIFRA. Without this exemption, sale and distribution 
of plants containing those modifications would require registration 
under FIFRA.
    Furthermore, PIPs from sexually compatible plants have been exempt 
under 40 CFR 174.25 for over 20 years. Had a developer sought 
confirmation that their conventionally bred, disease-resistant plant 
was exempt, EPA would have exempted such a product under 40 CFR 174.25 
on the basis that it is a PIP trait that has been created via 
conventional breeding. (See e.g., 66 FR 37772; July 19, 2001 (FRL-6057-
7)). This determination would be made without making a distinction of 
mode of action (e.g., gene loss-of-function or production of a 
protein). Disease-resistant traits are often caused by the loss-of-
function of a gene, and the 2001 preamble focused on the presence of a 
pesticidal trait (i.e., disease resistance) and claims of resistance in 
its determinations that such a trait would be considered a pesticide 
and a PIP, indicating that EPA did not make a distinction as to whether 
the disease-resistant trait was conferred via a gene loss-of-function 
or via production of a proteinaceous substance. Therefore, it is 
consistent to consider loss-of-function traits to be both pesticides 
and PIPs.
2. Criteria for the Exemption Specific to ``Loss-of-Function PIPs''
    EPA received several comments from industry, trade, and academia on 
the criterion of substance identity, requesting that the exemptions 
should be broadened to include non-identical pesticidal substances. By 
creating a separate exemption for ``loss-of-function PIPs'' with 
specific criteria and an accompanying definition, EPA finds that 
``loss-of-function PIPs'' as described by 40 CFR 174.27 do not require 
the ``identical substance'' criterion, as do PIPs exempt under 40 CFR 
174.26, due to fundamental differences in the pesticidal activity of 
``loss-of-function PIPs'' compared to PIPs exempt under 40 CFR 174.26.
    ``Loss-of-function PIPs'' are characterized by a modification that 
leads to the reduction or elimination of the activity of that gene, 
which then results in a pesticidal trait (e.g., the inactivation of a 
gene coding for a plant receptor confers disease resistance). Mutations 
that lead to a loss of gene function occur naturally and are prevalent 
within many organisms, including plants. For example, one study of 
1,071 genomes of the model plant Arabidopsis thaliana showed a total of 
60,819 loss-of-function variants within 12,907 genes, out of a genome-
wide total of approximately 25,500 genes (Refs. 12, 13). In addition to 
their natural occurrence as a result of various biotic and abiotic 
factors, plant breeders have intentionally induced these types of 
mutations during the conventional breeding process. One example is the 
treatment of seeds by chemical mutagens, which is a technique used by 
breeders to create new plant varieties (Refs. 14, 15).
    The traits that may result from the loss of function of a gene are 
diverse, ranging from altered grain size, increased drought tolerance, 
and resistance to plant diseases (Refs. 16-20). Disease resistance in 
plants from the loss of function of S-genes (susceptibility genes) have 
been identified in natural plant populations, and researchers have used 
knowledge about naturally occurring gene variants to create pest 
resistance in various plant species using genetic engineering (Refs. 
18, 19). For example, genetically engineered deletions in parts of the 
regulatory region of the SWEET14 gene in rice created a plant line that 
is resistant to the Xanthomonas oryzae pv. oryzae (Xoo) pathogen, and 
genetically engineered loss-of-function of eIF4E achieved potyvirus 
resistance in cucumber (Refs. 21, 22).
    As previously stated, EPA does not require an ``identical 
substance'' criterion for ``loss-of-function PIPs,'' and this is 
because mutations in any part of a gene have the potential to result in 
the loss of its function. Examples include deletions within the 
regulatory region that lead to the reduced expression (and thus reduced 
abundance) of an unmodified protein, or a single nucleotide change in 
the coding region, which can result in the creation of a premature stop 
codon, leading to the production of a shorter version of the protein 
originally encoded by that gene. Other changes to the coding region may 
also lead to mis-splicing of the pre-mRNA, which can subsequently 
result in the degradation of the pre-mRNA (no protein produced) or the 
production of a non-functional protein (Refs. 23, 24). If a non-
functional protein is produced, a normal part of routine biological 
processes is for the cell to recognize it as such and target it for 
degradation into its amino acid constituents. This turnover of protein 
occurs independent of how the non-functional protein was created, be it 
the result from a permanent genetic change (either through natural or 
induced mutation) or errors created when cells transcribe and/or 
translate the genetic code (Refs. 25-28). The ability of the cell to 
recognize and break down non-functional proteins is a routine cell 
function, and it enables the organism to be economical with its 
resources by reusing the amino acids for those proteins that do serve a 
purpose.
    Based on the prevalence of loss-of-function mutations in plants and 
the biological considerations of protein homeostasis, EPA finds that it 
does not need the same requirements on characteristics as it does for 
``PIPs created through genetic engineering from a sexually compatible 
plant.'' Therefore, ``loss-of-function PIPs,'' as exempted under 40 CFR 
174.27, are still supported by the risk assessment as presented in the 
proposed rule.
    As the ``loss-of-function PIP'' exemption is focused on function, 
there is no nucleic acid sequence requirement in the exemption criteria 
under 40 CFR 174.27 or in the exemption documentation under 40 CFR 
174.96. Commenters have stated a concern that

[[Page 34771]]

minor crops may face a disadvantage due to fewer genomic resources 
being available for their specific crop species. For example, one 
commenter stated that knowledge of genes in major crops or model 
organisms can inform the development of minor crops due to conserved 
gene function from a shared common ancestor, even when those plants are 
no longer sexually compatible. EPA believes that the codified exemption 
for ``loss-of-function PIPs'' with its focus on function will allow for 
use of this knowledge and provide a benefit for developers, including 
those of minor crops.

E. Eligibility Determination Process

1. Options To Determine Exemption Eligibility
    In the proposal, all exempted ``PIPs created through genetic 
engineering from a sexually compatible plant'' had the option of self-
determination. However, in the final rule, only developers of ``loss-
of-function PIPs'' (40 CFR 174.27) have the option to self-determine 
whether the exemption criteria are met.
    The Agency finds the approach to require an EPA confirmation for 
``PIPs created through genetic engineering from sexually compatible 
plants'' justified. Commenters felt that a mandatory EPA confirmation 
process would prevent an incorrect exemption determination. EPA agrees 
with commenters arguing that doing so will provide additional clarity 
to developers of ``PIPs created through genetic engineering from 
sexually compatible plants'' and increase transparency and public trust 
in products containing these PIPs.
    Other commenters were supportive of the flexibility that a 
mandatory self-determination process with a voluntary EPA confirmation 
process would provide. EPA acknowledges the value of this flexibility 
and has determined that developers of ``loss-of-function PIPs'' will 
have the option to either self-determine or request EPA confirmation of 
exemption eligibility. Given the straightforward nature of the criteria 
describing ``loss-of-function PIPs'' (i.e., a focus on function rather 
than source plant or underlying sequence), EPA believes it appropriate 
for ``loss-of-function PIPs'' to be eligible for the self-determination 
option as it is unlikely for a developer to accidentally mis-determine 
these PIPs. Furthermore, the mode of action of ``loss-of-function 
PIPs'' (i.e., reduction or elimination of an endogenous gene) is 
fundamentally different from ``PIPs created through genetic engineering 
from a sexually compatible plant'' (e.g., intentional production of a 
pesticidal protein), and as such, further lends itself to the 
availability of a self-determination option.
2. Extension of Exemption Status
    Commenters were largely supportive of the option to transfer the 
exemption status of a particular PIP to other plant varieties. 
Regarding this option, one commenter felt that the criterion in the 
proposal at 40 CFR 174.90(e)(1)(ii) that required that the same 
phenotype be created through non-homologous end joining repair 
modifications was too narrow. EPA agreed with this comment and, given 
the creation of a separate exemption for ``loss-of-function PIPs'' 
focused on function, was able to revise the exemption extension 
criteria for ``loss-of-function PIPs'' to be similarly focused on 
function (Unit III.C.1.).
3. Contents of a Self-Determination Letter
    In the proposal, EPA proposed to require submitters of self-
determination letters to identify the PIP (at proposed 40 CFR 
174.91(b)(2) and 40 CFR 174.91(b)(3)). Two commenters stated that EPA 
should require additional information on the PIP with the submission of 
a self-determination letter. Specifically, it was requested that EPA 
require information on the plant species, a description of the 
pesticidal trait, and a short summary of how the pesticidal trait was 
introduced into the plant variety. It was also requested that EPA 
require developers to submit information that would be required for an 
EPA confirmation. EPA agrees that information on the recipient plant 
species and a unique gene identifier should be included in the self-
determination letter and has updated the text at 40 CFR 174.91 to 
reflect this (Unit III.C.2.). Because the identity of the PIP may or 
may not include the name of the modified gene or plant species (e.g., 
the identity of the PIP could also be a trade name), the Agency has 
clarified that a gene identifier and the identity of the recipient 
plant must also be included in the submission of a self-determination 
letter.
    Regarding the other suggestions, such as a description of the 
pesticidal trait, a short summary of how the trait was introduced, and 
other information otherwise provided to the Agency as part of the EPA 
confirmation process, the Agency does not find this information 
necessary to be submitted with the self-determination letter. This is 
because the self-determination process does not involve an EPA review 
or confirmation. However, the information provided during an EPA 
confirmation is the same information required to be maintained by the 
recordkeeping requirements under 40 CFR 174.73, which equally applies 
to those submitting a self-determination of exemption. As part of the 
recordkeeping requirements, the information suggested by the commenters 
must already be made available to EPA upon request. Although the Agency 
is not requiring a summary description of the pesticidal trait and how 
it was introduced in the self-determination letter, the Agency agrees 
that identifying the trait type (e.g., insect resistance or disease 
resistance) would provide useful information for the public and for 
State level agencies and edited 40 CFR 174.91(b)(2) to reflect this. 
Thus, the language at 40 CFR 174.91(b)(2) now requires information on 
plant species, gene identifier, and trait type.
4. Documentation for an Exemption for ``PIPs Created Through Genetic 
Engineering From a Sexually Compatible Plant''
a. Scope of the Required Documentation
    EPA received comments on the scope of the documentation that is 
required to be produced to support an exemption for ``PIPs created 
through genetic engineering from a sexually compatible plant.'' One 
commenter requested that, in addition to discussing the categories of 
information needed to assess applicability of the exemption to a PIP, 
EPA furthermore establish expectations in the regulatory text on what 
information the Agency deems sufficient to satisfy each of the 
exemption criteria. In line with this, one commenter suggested to 
revise 40 CFR 174.95(a)(2) to replace ``information to demonstrate the 
recipient plant and the source plant are sexually compatible'' with 
``information to support that the recipient plant and the source plant 
are sexually compatible.'' The Agency agrees with this suggestion as a 
developer may, for example, provide a peer-reviewed literature 
rationale instead of generating empirical data to demonstrate that two 
plants are sexually compatible. The Agency revised the regulatory text 
in the final rule accordingly (Unit III.C.4.a.).
    The same commenter also suggested two revisions to 40 CFR 
174.95(c)(1). First, the commenter suggested that the documentation 
requirements should limit sequence comparison to nucleic acids, rather 
than require both the nucleic acid and the amino acid sequence for 
proteinaceous PIPs and to limit the nucleic acid sequence comparison to 
the location of the

[[Page 34772]]

intended modification(s) rather than the entire PIP. Second, the 
commenter requested that if an amino acid sequence was required, EPA 
further clarify the language on the sequence requirements to state 
``nucleotide sequence and deduced amino acid sequence.'' EPA has 
revised the text at 40 CFR 174.95(c)(1) for increased clarity as to the 
required sequence information based on the relevant comparator, i.e., 
the specific comparator at 40 CFR 174.95(c) is now listed based on the 
corresponding exemption category at 40 CFR 174.26. The Agency maintains 
that the entire nucleic acid sequence must be provided for all PIPs 
exempted under 174.26(a), as both exemptions at 40 CFR 174.26(a) allow 
for modifications in the regulatory regions. Thus, providing EPA with 
the nucleic acid sequence of the entire gene will allow the 
determination if the modifications meet the exemption requirements 
(Unit III.C.4.a.). The Agency maintains that the full-length amino acid 
sequence must additionally be provided for proteinaceous PIPs but 
agrees with the commenter that the deduced amino acid sequence would be 
sufficient to inform the identity of that PIP in these instances.
    Commenters requested that EPA exclude wild relatives as potential 
source plants and/or impose geographic restrictions on source plants, 
noting that non-target organisms living within the range of the wild 
donor plants would have adapted to exposures from these wild plants and 
that non-target organisms from outside this range may therefore be 
negatively impacted by a PIP from the wild plant due to lack of 
previous exposure. Additionally, it was noted that allowing sexually 
compatible wild relatives as source plants may result in toxins from 
these plants being missed as part of the plant breeder screening.
    EPA understands that wild relatives provide an important source of 
genetic variation for developers and therefore has chosen not to 
exclude them from use as sexually compatible source plants for exempt 
PIPs. However, to address the concern raised by the commenters, EPA has 
added a requirement at 40 CFR 174.95(d)(2) that if the source plant is 
a wild relative of the recipient plant, the developer must describe why 
the PIP is not anticipated to pose a hazard to humans or the 
environment. EPA provides a list in the regulatory text at 40 CFR 
174.95(d)(2) of the types of information that can be used to describe 
why a PIP is not anticipated to pose a hazard to humans or the 
environment.
b. Feasibility To Meet the PIP Expression Criteria and Develop Adequate 
Documentation
    EPA received several comments on the proposed rule regarding the 
PIP expression criteria at 40 CFR 174.26(b) and the associated 
documentation requirements at 40 CFR 174.95(c)(2). Several commenters 
raised concerns that meeting the documentation requirements would be 
impractical and cost prohibitive given the large variation in plant 
gene expression between tissues and growth stages, especially when 
considering gene expression in different environmental conditions. One 
commenter submitted that data to meet the expression limitation 
exemption criteria should only be required if the intent of the 
modification is to increase levels of the expressed pesticidal 
substance. This approach is consistent with the Agency's analysis of 
gene expression articulated in the proposal. Specifically, EPA found 
that although variations in the production of plant substances will 
occur in response to environmental conditions, there are physiological 
and practical considerations that limit the expression level, and thus 
the abundance of a particular substance in plants that are sexually 
compatible. EPA finds that this is especially true for regulatory 
regions and polymorphic sequences that are present in regulatory 
regions that are moved between native alleles. In other words, there is 
the expectation that the expression pattern of a PIP would be within 
that what is found within the sexually compatible population, so long 
as it is under the control of the regulatory elements found within a 
native allele.
    Consistent with this assessment and taking into consideration the 
comments received on the impracticality and potential financial burden 
of determining the expression levels to comply with proposed 40 CFR 
174.95(c)(2), the Agency removed the exemption criterion at proposed 40 
CFR 174.26(a)(2)(i) that would have allowed modifications to regulatory 
regions for the purpose of altering the expression level of a 
pesticidal substance. Instead, EPA is now requiring at 40 CFR 
174.26(a)(1) that any regulatory region that is inserted as part of a 
native gene must be identical in nucleotide sequence to the regulatory 
region of the native gene as it is identified in the source plant. 
Similarly, 40 CFR 174.26(a)(2) allows regulatory region changes only 
based on polymorphic sequence(s) identified in a native allele of the 
modified gene. In making these revisions to 40 CFR 174.26, EPA is able 
to remove the requirements for expression profile confirmation at 
proposed 40 CFR 174.95(c)(2), as the expectation is that the expression 
profiles of PIPs that meet these exemption criteria at 40 CFR 174.26(a) 
will not be outside of that what is found within the sexually 
compatible population of the recipient plant.
5. Activities That Require Submission of an Eligibility Determination
    Two commenters requested clarification on which activities may 
require a separate notification of self-determination for a PIP under 
40 CFR 174.541. Specifically, commenters requested clarification in 
those instances in which a plant containing the PIP is imported to the 
United States for the distribution in commerce for consumption or 
planting in the absence of a tolerance or tolerance exemption granted 
under FFDCA.
    EPA is confirming that the Agency is requiring a separate 
eligibility determination under 40 CFR 174.541 for residues of those 
PIPs that are imported into the United States and that are used for 
food or feed if the developer has not already obtained an exemption 
under 40 CFR 174.21. As discussed in the preamble of the proposed rule, 
a separate submission of the eligibility determination of the FFDCA 
exemption for a PIP proposed for use in food or feed is required only 
if it has not already been submitted under FIFRA. To clarify, EPA has 
added a new paragraph (g) to 40 CFR 174.90, which explains that a 
duplicative eligibility submission is not required for purposes of 40 
CFR 174.541(c), if it is already being submitted for purposes of 40 CFR 
174.21(d). The proposal discussed one such scenario where this might be 
the case (e.g., Unit VI.C.1. of the proposed rule). Briefly, a 
developer will need an exemption eligibility determination for the 
purposes of FFDCA but not FIFRA when residues of a PIP will be in or on 
food imported into the United States, but the PIP is not intended to be 
sold or distributed for pesticidal use (e.g., PIP containing seed or 
plant sold for planting) in the United States. In that case, the PIP 
residues in the imported food would need a tolerance or tolerance 
exemption to allow for distribution in interstate commerce in the 
United States under the FFDCA, but would not need a FIFRA exemption 
since it is not intended to be sold or distributed for pesticidal 
purposes in the United States.
    Other commenters inquired whether testing of PIPs at or under 10 
acres of land would require an Experimental Use Permit (EUP) under 
FIFRA section 5 and

[[Page 34773]]

therefore whether an eligibility determination for certain PIPs would 
be required at these acreages. 40 CFR 172.3 applies to PIPs. As 
described in 40 CFR 172.3, tests on 10 acres or less are presumed to 
not require an EUP so long as any food or feed crops involved in, or 
affected by, such tests (including, but not limited to, crops 
subsequently grown on such land which may reasonably be expected to 
contain residues of the tested pesticides) are destroyed or consumed 
only by experimental animals unless an appropriate tolerance or 
exemption from a tolerance has been established under FFDCA for 
residues of the pesticide. Further, pursuant to 40 CFR 172.3(e), EPA 
may, on a case-by-case basis, require that testing be carried out under 
an EUP even if such testing involves 10 acres or less. For a PIP 
subject to this rulemaking that would be used in testing taking place 
on 10 acres or less to be able to take advantage of the presumption in 
40 CFR 172.3, that PIP would need to either demonstrate that the 
appropriate tolerance or exemption has been established or follow the 
requirements of crop destruction. Pursuant to subpart E of 40 CFR 174 
as codified in this rule, for PIPs exempted under 40 CFR 174.26, 
demonstrating that the tolerance exemption at section 40 CFR 174.541 
applied would require an EPA confirmation, and for PIPs exempted under 
40 CFR 174.27, it would require the submission of a self-determination. 
For a PIP for which a tolerance exemption has not been established, in 
addition to requirements of crop destruction for field testing at or 
under 10 acres, EPA previously published and still relies on guidance 
(Ref. 29) detailing containment measures to restrict the flow of 
genetic material, including seeds, from field tests to minimize the 
potential for PIP residues that do not have a tolerance exemption to 
enter the food supply. These additional considerations are crucial to 
prevent PIPs lacking a tolerance exemption from entering the food 
supply and the consequences of adulteration under FFDCA. EPA notes that 
it is expecting to provide an update to the information and/or process 
provided in PRN 2007-2 (Ref. 29) regarding measures needed for 
containing small-scale testing of PIPs in light of changes in 
regulatory oversight due to USDA's recently revised 7 CFR part 340 
regulations.
6. Submitting Confidential Business Information (CBI)
    Several commenters noted that information included in a request for 
EPA confirmation may be classified as CBI and requested assurance and 
clarification for how EPA would protect intellectual property and other 
proprietary information. As EPA is using its existing electronic 
reporting site for receiving submissions, this information will be 
transmitted to EPA in a secure manner. As stated in 40 CFR 174.90(c), 
any claims of confidentiality for information submitted in the request 
for EPA confirmation must be made in accordance with the procedures 
outlined in 40 CFR 174.9 of subpart A. 40 CFR 174.9 instructs a 
submitter on how to claim data or other information as CBI. Information 
likely to be claimed as CBI may be part of the documentation for an 
exemption (e.g., sequence information on the pesticidal substance). 
Developers also have the option to claim information submitted as part 
of the self-determination as CBI (e.g., gene ID, plant species). 
However, it is important to note that every individual piece of 
information claimed as CBI must be supported by its own substantiation. 
For this reason, and for reasons of public transparency, as it has for 
all PIPs, EPA continues to encourage PIP developers to limit their 
claims to CBI to only the most pertinent pieces of information.

F. Endangered Species Assessment

    EPA received public comment regarding whether the proposed 
exemption may affect endangered species. EPA determined that this 
action invokes obligations under the Endangered Species Act because 
this is a discretionary action that exempts certain pesticidal 
substances from some requirements under FIFRA, such that the exemptions 
could cause potential exposures in the environment. Therefore, EPA 
conducted an Endangered Species Assessment for ``PIPs created through 
genetic engineering from a sexually compatible plant'' and for ``loss-
of-function PIPs.''
    In the proposed rule, after careful consideration of potential 
interactions that the PIPs proposed for exemption may have with 
nontarget organisms (see Unit VI.A.3. of the proposed rule), EPA 
preliminarily determined that use of the PIPs proposed for exemption is 
not likely to cause unreasonable adverse effects on the environment and 
humans in the absence of regulatory oversight (although ``regulatory 
oversight'' still exists in the form of the adverse effects reporting 
requirement in existing 40 CFR 174.71) resulting in a reasonable 
expectation that no discernible effects to nontarget organisms will 
occur. As no discernible effects to nontarget organisms are reasonably 
expected to occur due to the use of these PIPs, which necessarily 
includes any threatened or endangered species (listed species), EPA 
therefore reaches a ''No Effect'' determination for listed species and 
their critical habitats.
    Herein, EPA provides brief summaries of key considerations used in 
the Agency's determination that the PIP exemptions proposed in the 2020 
preamble and finalized in this rule are reasonably expected to result 
in no discernable effects to nontarget organisms, including listed 
species. In the proposed rule, EPA considered several factors in 
determining whether PIPs that meet the criteria under proposed 40 CFR 
174.26 could be exempted from FIFRA requirements in order to meet the 
40 CFR 174.21(a) requirement (Unit VI.A.3.h. of the proposed rule). In 
its assessment, the Agency relied on the large body of knowledge that 
currently exists on sexually compatible plants and genetic diversity. 
Briefly, with regard to the potential ecological effects, the Agency 
found that there is: ``(1) Low potential for novel exposures; (2) Low 
potential for levels of ``PIPs created through genetic engineering from 
a sexually compatible plant'' to exceed levels found in sexually 
compatible plants; and (3) Low potential for ``PIPs created through 
genetic engineering from a sexually compatible plant'' to move from 
cultivated plants to wild or weedy relatives through gene flow and 
increase weediness.'' (Unit VI.A.3. of the proposed rule). EPA also 
evaluated considerations specific to newer biotechnology techniques 
related to the PIPs proposed for exemption and found that their use in 
creating these PIPs would pose negligible risk to the environment. 
Lastly, the Agency found that the likelihood is negligible that the 
transfer of a PIP via biotechnology from a nonagricultural (wild) 
relative to an agricultural one would pose a greater risk than if it 
were transferred through conventional breeding.
    In summary, PIPs that are exempted under 40 CFR 174.26 represent a 
subset of substances already present in related plants and are 
equivalent both in identity and in expression profile (how much, where, 
and when the substances are expressed in plants). As ``loss-of-function 
PIPs'' exempted under 40 CFR 174.27 were originally proposed as a 
subcategory of PIPs exempted under 40 CFR 174.26, they too fall within 
the scope of the Agency's analysis in the proposed rule preamble. 
Pesticidal traits resulting from the loss-of-function of an endogenous 
gene are common occurrences in wild plants and in conventional breeding 
(Refs. 18, 19) and EPA finds that there is no potential for

[[Page 34774]]

novel exposures or hazards for ``loss-of-function PIPs,'' as this group 
of PIPs is characterized by a modification that leads to the reduction 
or elimination of the activity of a gene that had already been present 
in the recipient plant. As the PIPs exempted under this rule are 
considered to be equivalent to those already found in nature and used 
in conventional breeding, there is a reasonable expectation that no 
discernible effects to listed species will occur from their use. As no 
discernible effects are reasonably expected to occur to listed species 
due to the use of these PIPs, EPA therefore reaches a ''No Effect'' 
determination for listed species and their critical habitats.

VII. References

    The following is a listing of the documents that are specifically 
referenced in this document. The docket includes these documents and 
other information considered by EPA, including documents that are 
referenced within the documents that are included in the docket, even 
if the referenced document is not physically located in the docket. For 
assistance in locating these other documents, please consult the person 
listed under FOR FURTHER INFORMATION CONTACT.

1. Response to Comments to the Proposed Rule to Exempt Certain 
Plant-Incorporated Protectants (PIPs) Derived from Newer 
Technologies. Available at https://www.regulations.gov under Docket 
ID No. EPA-HQ-OPP-2019-0508.
2. USEPA. 2020. Pesticides; Exemptions of Certain Plant-Incorporated 
Protectants (PIPs) Derived from Newer Technologies. 85 FR 64308, 
October 9, 2020 (FRL-10014-10). Available at https://www.regulations.gov under Docket ID No. EPA-HQ-OPP-2019-0508.
3. USEPA, USFDA, and USDA. Modernizing the Regulatory System for 
Biotechnology Products: Final Version of the 2017 Update to the 
Coordinated Framework for the Regulation of Biotechnology. 2017; 
Available from: https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/update-coordinated-framework-regulation-biotechnology.
4. USEPA. 2022. Cost Analysis For the Final Rule Exempting Certain 
Plant-Incorporated Protectants (PIPs) from Registration. Available 
at https://www.regulations.gov under Docket ID No. EPA-HQ-OPP-2019-
0508.
5. Mhoswa L., O'Neill M.M., Mphahlele M.M., Oates C.N., Payn K.G., 
Slippers B., Myburg A.A., and Naidoo S. A Genome-Wide Association 
Study for Resistance to the Insect Pest Leptocybe invasa in 
Eucalyptus grandis Reveals Genomic Regions and Positional Candidate 
Defense Genes. Plant and Cell Physiology. 2020. 61(7), pp.1285-96.
6. Jamie, Gabriel A., and Joana I. Meier. The persistence of 
polymorphisms across species radiations. Trends in Ecology & 
Evolution. 2020. 35(9), pp.795-808.
7. Pesticide Registration (PR) Notice 2011-3. Standard Format for 
Data Submitted Under the Federal Insecticide, Fungicide, and 
Rodenticide Act (FIFRA) and Certain Provisions of the Federal Food, 
Drug, and Cosmetic Act (FFDCA), November 2011. Available online at 
https://www.epa.gov/sites/default/files/2014-04/documents/pr2011-3.pdf.
8. USEPA Federal Register. 2001. Regulation Under the Federal 
Insecticide, Fungicide, and Rodenticide Act for Plant-Incorporated 
Protectants (Formerly Plant-Pesticides). 66 FR 37772, July 19, 2001 
(FRL-6057-7). Available online at https://archive.epa.gov/pesticides/biopesticides/web/pdf/pip_rule.pdf.
9. Kaiser, N., Douches, D., Dhingra, A., Glenn, K.C., Herzig, P.R., 
Stowe, E.C., and Swarup, S. The role of conventional plant breeding 
in ensuring safe levels of naturally occuring toxins in food crops. 
Trends in Food Science & Technology. 2020. 100, pp.51-66.
10. Graham, N., Patil, G.B., Bubeck, D.M., Dobert, R.C., Glenn, 
K.C., Gutsche, A.T., Kumar, S., Lindbo, J.A., Maas, L., May, G.D. 
and Vega-Sanchez, M.E. Plant genome editing and the relevance of 
off-target changes. Plant Physiology. 2020. 183(4), pp.1453-1471.
11. Hartl, D.L., A primer of population genetics. 3rd ed. 2000, 
Sunderland, MA: Sinauer Associates, Inc.
12. Xu, Y.C., Niu, X.M., Li, X.X., He, W., Chen, J.F., Zou, Y.P., 
Wu, Q., Zhang, Y.E., Busch, W. and Guo, Y.L., 2019. Adaptation and 
phenotypic diversification in Arabidopsis through loss-of-function 
mutations in protein-coding genes. The Plant Cell, 31(5), pp.1012-
1025.
13. Kaul, S., Koo, H.L., Jenkins, J., Rizzo, M., Rooney, T., Tallon, 
L.J., Feldblyum, T., Nierman, W., Benito, M.I., Lin, X. and Town, 
C.D., 2000. Analysis of the genome sequence of the flowering plant 
Arabidopsis thaliana. Nature, 408(6814), pp.796-815.
14. Oladosu, Y., Rafii, M.Y., Abdullah, N., Hussin, G., Ramli, A., 
Rahim, H.A., Miah, G. and Usman, M., 2016. Principle and application 
of plant mutagenesis in crop improvement: a review. Biotechnology & 
Biotechnological Equipment, 30(1), pp.1-16.
15. Jankowicz-Cieslak, J., Mba, C. and Till, B.J., 2017. Mutagenesis 
for crop breeding and functional genomics. In Biotechnologies for 
plant mutation breeding (pp.3-18). Springer, Cham.
16. Duan, P., Xu, J., Zeng, D., Zhang, B., Geng, M., Zhang, G., 
Huang, K., Huang, L., Xu, R., Ge, S. and Qian, Q., 2017. Natural 
variation in the promoter of GSE5 contributes to grain size 
diversity in rice. Molecular plant, 10(5), pp.685-694.
17. Monroe, J.G., Powell, T., Price, N., Mullen, J.L., Howard, A., 
Evans, K., Lovell, J.T. and McKay, J.K., 2018. Drought adaptation in 
Arabidopsis thaliana by extensive genetic loss-of-function. Elife, 
7.
18. Bai, Y., Pavan, S., Zheng, Z., Zappel, N.F., Reinst[auml]dler, 
A., Lotti, C., De Giovanni, C., Ricciardi, L., Lindhout, P., Visser, 
R. and Theres, K., 2008. Naturally occurring broad-spectrum powdery 
mildew resistance in a Central American tomato accession is caused 
by loss of Mlo function. Molecular Plant-Microbe Interactions, 
21(1), pp.30-39.
19. Acevedo[hyphen]Garcia, J., Kusch, S. and Panstruga, R., 2014. 
Magical mystery tour: MLO proteins in plant immunity and beyond. New 
Phytologist, 204(2), pp.273-281.
20. Van de Wiel, C.C.M., Schaart, J.G., Lotz, L.A.P. and Smulders, 
M.J.M. New traits in crops produced by genome editing techniques 
based on deletions. Plant biotechnology reports. 2017. 11(1), pp.1-
8.
21. Li, T., Liu, B., Spalding, M.H., Weeks, D.P. and Yang, B., 2012. 
High-efficiency TALEN-based gene editing produces disease-resistant 
rice. Nature biotechnology, 30(5), pp.390-392.
22. Chandrasekaran, J., Brumin, M., Wolf, D., Leibman, D., Klap, C., 
Pearlsman, M., Sherman, A., Arazi, T. and Gal[hyphen]On, A., 2016. 
Development of broad virus resistance in non[hyphen]transgenic 
cucumber using CRISPR/Cas9 technology. Molecular plant pathology, 
17(7), pp.1140-1153.
23. Reddy A.S.N., Marquez Y., Kalyna M., and Barta A. Complexity of 
the alternative splicing landscape in plants. The Plant Cell. 2013. 
25(10), pp.3657-83.
24. Roy SW, Irimia M. Intron mis-splicing: no alternative?. Genome 
biology. 2008. 9(2), pp.1-3.
25. Merchante, C., Stepanova A. N., and Alonso J. M. Translation 
regulation in plants: an interesting past, an exciting present and a 
promising future. The Plant Journal. 2017. 90, pp. 628-653.
26. Gordon A.J., Satory D., Halliday J.A., and Herman C. Lost in 
transcription: transient errors in information transfer. Current 
opinion in microbiology. 2015. 24, pp.80-7.
27. Li L., Nelson C.J., Tr[ouml]sch J., Castleden I., and Huang S., 
Millar A.H. Protein degradation rate in Arabidopsis thaliana leaf 
growth and development. The Plant Cell. 2017. 29(2), pp.207-28.
28. Toyama B.H. and Hetzer M.W. Protein homeostasis: live long, 
won't prosper. Nature reviews Molecular cell biology. 2013. 14(1), 
pp.55-61.
29. Pesticide Registration (PR) Notice 2007-2: Guidance on Small-
Scale Field Testing and Low-level Presence in Food of Plant-
incorporated Protectants (PIPs), April 30, 2007. Available online at 
https://www.epa.gov/pesticide-registration/prn-2007-2-guidance-small-scale-field-testing-and-low-level-presence-food.
30. USEPA. Supporting Statement for the Information Collection 
Request (ICR) entitled: Exemptions of Certain Plant-Incorporated 
Protectants (PIPs) Derived from Newer Technologies Rulemaking (Final 
Rule; RIN 2070-AK54). EPA ICR No.: 2619.02; OMB Control No. 2070-
0214. (May 2023).

[[Page 34775]]

VIII. FIFRA Review Requirements

    Pursuant to FIFRA section 25(a), EPA submitted the draft final rule 
to the United States Department of Agriculture (USDA) for review, with 
a copy sent to the appropriate Congressional Committees as required 
under FIFRA section 25(a). The Agency did not receive any comments from 
USDA.
    In accordance with FIFRA section 25(d), the EPA asked the FIFRA 
Scientific Advisory Panel (SAP) to waive review of the draft final 
rule, as was done for the draft proposed rule. The FIFRA SAP waived its 
scientific review of the draft final rule on October 12, 2022, because 
the rule does not raise scientific or science policy issues that 
warrant a scientific review by the SAP.

IX. Statutory and Executive Order Reviews

    Additional information about these statutes and Executive Orders 
can be found at https://www.epa.gov/laws-regulations/laws-and-executive-orders.

A. Executive Orders 12866: Regulatory Planning and Review and 14094: 
Modernizing Regulatory Review

    This action is a significant regulatory action that was submitted 
to the Office of Management and Budget (OMB) for review under Executive 
Order 12866 (58 FR 51735, October 4, 1993), as amended by Executive 
Order 14094 (88 FR 21879, April 11, 2023). Any changes made in response 
to OMB recommendations during that review have been documented in the 
docket. EPA prepared an analysis of the potential costs and benefits 
associated with this action (Ref. 4) which is summarized in more detail 
in Unit I.E., and included in the docket.

B. Paperwork Reduction Act (PRA)

    The information collection activities in this rule have been 
submitted for approval to OMB under the PRA, 44 U.S.C. 3501 et seq. The 
Information Collection Request (ICR) document that EPA prepared is 
assigned EPA ICR No. 2619.02 (Ref. 30), and identified by OMB Control 
No. 2070-0214. You can find a copy of the ICR in the docket for this 
rule, and it is briefly summarized here. The information collection 
requirements are not enforceable until OMB approves them.
    The information collection activities in this rule are associated 
with the exemption eligibility process (i.e., self-determination, 
request for EPA confirmation, and associated recordkeeping) established 
in this rule as an alternative to the existing pesticide registration 
and tolerance activities that are currently approved by OMB under OMB 
Control No. 2070-0060 (EPA ICR No. 0277.23), OMB Control No. 2070-0142 
(EPA ICR No. 1693.10), OMB Control No. 2070-0028 (EPA ICR No. 0143.13, 
and OMB Control No. 2070-0024 (EPA ICR No. 0597.13). Once this ICR is 
approved, EPA intends to amend the ICR approved by OMB under OMB 
Control No. 2070-0060 (EPA ICR No. 0277.23) to incorporate the 
information collection activities and burden attributable to this rule.
    Respondents/affected entities: See Unit I.A.
    Respondent's obligation to respond: Required to obtain the 
exemption (40 CFR part 174).
    Frequency of response: On occasion.
    Total estimated number of respondents: 10.
    Total estimated number of responses: 10 (per year), which reflects 
an estimate of 1 response per respondent each year. The ICR accounts 
for the most conservative burden estimate, which the Agency projects 
will be up to 10 submissions per year.
    Total estimated burden: 850 hours (per year), which reflects an 
approximate burden of 85 hours per submission. Burden is defined at 5 
CFR 1320.3(b).
    Total estimated cost: $125,800 (per year), includes $0 annualized 
capital or operation and maintenance costs.
    An Agency may not conduct or sponsor, and a person is not required 
to respond to, a collection of information unless it displays a 
currently valid OMB control number. The OMB control numbers for EPA's 
regulations in 40 CFR are listed in 40 CFR part 9. When OMB approves 
this ICR, the Agency will announce that approval in the Federal 
Register and publish a technical amendment to 40 CFR part 9 to display 
the OMB control number for the approved information collection 
activities contained in this final rule.

C. Regulatory Flexibility Act (RFA)

    I certify that this action will not have a significant economic 
impact on a substantial number of small entities under the RFA, 5 
U.S.C. 601 et seq. In making this determination, EPA concludes that the 
impact of concern for this rule is any significant adverse economic 
impact on small entities and that the Agency is certifying that this 
rule will not have a significant economic impact on a substantial 
number of small entities because the rule relieves regulatory burden on 
the small entities subject to the rule. The rule is expected to reduce 
costs to developers of ``PIPs created through genetic engineering from 
a sexually compatible plant'' and ``loss-of-function PIPs,'' and the 
cost savings per product are approximately $472,000-$886,000. The cost 
savings per product will be realized when the developer submits a 
letter of self-determination or requests EPA confirmation, as 
applicable. The exemption for ``PIPs created through genetic 
engineering from a sexually compatible plant'' and ``loss-of-function 
PIPs'' reduces the costs associated with meeting regulatory 
requirements for these types of PIPs and therefore removes a potential 
barrier to market entry for small entities. Of the entities likely to 
develop PIPs that meet the exemptions outlined in this rulemaking, EPA 
currently estimates that approximately 80% are small entities.
    I have therefore concluded that this action will relieve regulatory 
burden for all directly regulated small entities. The basis for this 
determination is presented in the small entity analysis prepared as 
part of the cost analysis for this rulemaking (Ref. 4), which is 
summarized in Unit I.E., and a copy is available in the docket.

D. Unfunded Mandates Reform Act (UMRA)

    This action does not contain an unfunded mandate of $100 million or 
more as described in UMRA, 2 U.S.C. 1531-1538, and does not 
significantly or uniquely affect small governments. This action is not 
expected to impose an enforceable duty on any State, local or Tribal 
governments, and the requirements imposed on the private sector are not 
expected to result in annual expenditures of $100 million or more. 
Accordingly, EPA has determined that the requirements of sections 202, 
203, or 205 do not apply to this action.

E. Executive Order 13132: Federalism

    This action does not have federalism implications as specified in 
Executive Order 13132 (64 FR 43255, August 10, 1999), because it will 
not have substantial direct effects on the states, on the relationship 
between the national government and the states, or on the distribution 
of power and responsibilities among the various levels of government. 
Thus, Executive Order 13132 does not apply to this action.

F. Executive Order 13175: Consultation and Coordination With Indian 
Tribal Governments

    This action does not have Tribal implications as specified in 
Executive Order 13175 (65 FR 67249, November 9, 2000), because it will 
not have substantial direct effects on Tribal governments, on the 
relationship

[[Page 34776]]

between the Federal Government and the Indian Tribes, or on the 
distribution of power and responsibilities between the Federal 
Government and Indian Tribes. Thus, Executive Order 13175 does not 
apply to this action.

G. Executive Order 13045: Protection of Children From Environmental 
Health Risks and Safety Risks

    EPA interprets Executive Order 13045 (62 FR 19885, April 23, 1997) 
as applying to those regulatory actions that concern environmental 
health or safety risks that the EPA has reason to believe may 
disproportionately affect children, per the definition of ``covered 
regulatory action'' in section 2-202 of the Executive Order. This 
action is not subject to Executive Order 13045 because it does not 
concern an environmental health risk or safety risk.

H. Executive Order 13211: Actions Concerning Regulations That 
Significantly Affect Energy Supply, Distribution or Use

    This action is not a ``significant energy action'' as defined in 
Executive Order 13211 (66 FR 28355, May 22, 2001), because it is not 
likely to have a significant adverse effect on the supply, distribution 
or use of energy and has not otherwise been designated as a significant 
energy action by the Administrator of the Office of Information and 
Regulatory Affairs.

I. National Technology Transfer Advancement Act (NTTAA)

    This action does not involve technical standards that would require 
Agency consideration under NTTAA section 12(d), 15 U.S.C. 272.

J. Executive Order 12898: Federal Actions To Address Environmental 
Justice in Minority Populations and Low-Income Populations and Low-
Income Populations

    Executive Order 12898 (59 FR 7629, February 16, 1994) directs 
Federal agencies, to the greatest extent practicable and permitted by 
law, to make environmental justice part of their mission by identifying 
and addressing, as appropriate, disproportionately high and adverse 
human health or environmental effects of their programs, policies, and 
activities on minority populations (people of color and/or indigenous 
peoples) and low-income populations.
    EPA believes that this type of action does not concern human health 
or environmental conditions and therefore cannot be evaluated with 
respect to potentially disproportionate and adverse effects on people 
of color, low-income populations and/or indigenous peoples. Although 
this action does not concern human health or environmental conditions, 
EPA considered potential environmental justice concerns during the 
development of the proposed rule, sought comments specifically on this 
point with regard to the proposed exemptions, and finds that this 
action will not result in disproportionately high and adverse human 
health, environmental, climate-related, or other cumulative impacts on 
disadvantaged communities.

K. Congressional Review Act (CRA)

    This action is subject to the CRA, 5 U.S.C. 801 et seq., and EPA 
will submit a rule report to each House of the Congress and to the 
Comptroller General of the United States. This action is not a ``major 
rule'' as defined by 5 U.S.C. 804(2).

L. Executive Orders 13874: Modernizing the Regulatory Framework for 
Agricultural Biotechnology Products and 14801: Advancing Biotechnology 
and Biomanufacturing Innovation for a Sustainable, Safe, and Secure 
American Bioeconomy

    This action is intended to further implement section 4(b) of 
Executive Order 13874 (84 FR 27899, June 11, 2019), and section 8 of 
Executive Order 14801 (87 FR 56849, September 12, 2022). This final 
rule may promote future innovation and competitiveness by efficiently 
exempting through regulation qualifying ``PIPs created through genetic 
engineering from a sexually compatible plant'' and ``loss-of-function 
PIPs'' that meet the FIFRA and FFDCA standards for exemption.

List of Subjects in 40 CFR Part 174

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Plant-incorporated 
protectants, Reporting and recordkeeping requirements.

Michael S. Regan,
Administrator.

    Therefore, for the reasons stated in the preamble, 40 CFR part 174 
is amended as follows:

PART 174--PROCEDURES AND REQUIREMENTS FOR PLANT-INCORPORATED 
PROTECTANTS

0
1. The authority citation for part 174 continues to read as follows:

    Authority:  7 U.S.C. 136-136y; 21 U.S.C. 321(q), 346a and 371.


0
2. Amend Sec.  174.3 by adding in alphabetical order definitions for 
``Gene'', ``Genetic engineering'', ``Loss-of-function plant-
incorporated protectant'', ``Native allele'', and ``Native gene'' and 
revising the definition of ``Sexually compatible'' to read as follows:


Sec.  174.3  Definitions.

* * * * *
    Gene, and other grammatical variants such as ``genic,'' means a 
unit of heritable genetic material that is comprised of the genetic 
material necessary for the production of a substance.
    Genetic engineering means the modification of the genome of an 
organism using recombinant, synthesized, or amplified nucleic acids or 
other techniques excluded from the definition of conventional breeding.
* * * * *
    Loss-of-function plant-incorporated protectant means a plant-
incorporated protectant in which the genetic material of a native gene 
is modified to result in a pesticidal effect through the reduction or 
elimination of the activity of that gene. For purposes of loss-of-
function plant-incorporated protectants, the active ingredient and 
pesticidal substance are one and the same and are defined as the 
genetic material that has been modified to create the pesticidal trait 
(i.e., modification of the sequence of nucleic acids). Loss-of-function 
plant-incorporated protectants do not include instances where the 
reduction or elimination of the activity of the modified native gene 
results in the intentional increase of activity of another pesticidal 
gene.
    Native allele means a variant of a native gene that is identified 
in the genetic diversity of plants sexually compatible with the 
recipient plant.
    Native gene means a gene that is identified in the recipient plant 
or source plants that are sexually compatible with the recipient plant. 
It does not include genes introduced through genetic engineering from a 
source organism that is not sexually compatible with the source plant.
* * * * *
    Sexually compatible, when referring to plants, means plants must be 
capable of forming a viable zygote through the union of two gametes 
through conventional breeding.
* * * * *

0
3. Revise Sec.  174.21 to read as follows:


Sec.  174.21  General qualifications for exemptions.

    A plant-incorporated protectant is exempt from the requirements of 
FIFRA, other than the requirements of Sec.  174.71,

[[Page 34777]]

if it meets the exemption criteria in paragraphs (a) through (d) of 
this section. Plant-incorporated protectants that are not exempt from 
the requirements of FIFRA under this subpart are subject to all the 
requirements of FIFRA.
    (a) The active ingredient of the plant-incorporated protectant 
meets the exemption criteria listed in at least one of the sections in 
Sec. Sec.  174.25 through 174.50.
    (b) When the plant-incorporated protectant is intended to be 
produced and used in a crop used as food, the residues of the active 
ingredient of the plant-incorporated protectant are either exempted 
from the requirement of a tolerance under FFDCA (21 U.S.C. 321 et seq.) 
as listed in subpart W of this part, or no tolerance would otherwise be 
required.
    (c) Any inert ingredient that is part of the plant-incorporated 
protectant is listed as an approved inert ingredient in subpart X of 
this part.
    (d) For plant-incorporated protectants listed in the subparagraphs 
below, the exemption applies only if the developer is compliant with 
the general recordkeeping requirements specified in Sec.  174.73 per 
sections 8 and 9 of FIFRA, 7 U.S.C. 136f and 136g, and only after 
compliance with the relevant eligibility determination procedures 
specified in Sec.  174.90:
    (1) Plant-incorporated protectant created through genetic 
engineering from a sexually compatible plant.
    (2) Loss-of-function plant-incorporated protectant.

0
4. Amend Sec.  174.25 by revising the section heading and the 
introductory text and adding paragraph (c) to read as follows:


Sec.  174.25  Active ingredient of a plant-incorporated protectant from 
a sexually compatible plant created through conventional breeding.

    The active ingredient is exempt if all of the following conditions 
are met:
* * * * *
    (c) The genetic material is transferred from the source plant to 
the recipient plant only through conventional breeding.

0
5. Add Sec.  174.26 to subpart B to read as follows:


Sec.  174.26  Active ingredient of a plant-incorporated protectant 
created through genetic engineering from a sexually compatible plant.

    The active ingredient is exempt if the conditions in paragraphs (a) 
and (b) of this section are met.
    (a) The active ingredient is characteristic of the population of 
plants sexually compatible with the recipient plant and is created 
through genetic engineering from either an insertion of a native gene 
into the recipient plant as specified in paragraph (a)(1) of this 
section or a modification of an existing native gene in the recipient 
plant as specified in paragraph (a)(2) of this section.
    (1) Insertion. A native gene is inserted into the genome of the 
recipient plant and produces a pesticidal substance identical in 
sequence to the pesticidal substance identified in the source plant. 
The regulatory regions inserted as part of the native gene must be 
identical in nucleic acid sequence to those regulatory regions of the 
native gene identified in the source plant.
    (2) Modification. The existing native gene is modified to match 
corresponding polymorphic sequence(s) in a native allele of that gene 
using a single source plant as a template.
    (b) This exemption does not apply until the requirements in Sec.  
174.21(d) have been met.

0
6. Add Sec.  174.27 to subpart B to read as follows:


Sec.  174.27  Active ingredient of a loss-of-function plant-
incorporated protectant.

    The active ingredient is exempt if the following conditions are 
met:
    (a) The genetic material of a native gene is modified using genetic 
engineering to result in a pesticidal effect through the reduction or 
elimination of the activity of that gene; and
    (b) This exemption does not apply until the requirements in Sec.  
174.21(d) have been met.

0
7. Add Sec.  174.73 to subpart D to read as follows:


Sec.  174.73  General recordkeeping requirements for exemptions.

    For 5 years, starting with the effective date of a plant-
incorporated protectant exemption, any person who is required to submit 
documentation for the determination of eligibility for a plant-
incorporated protectant listed under Sec.  174.21(d) must do both of 
the following:
    (a) Maintain documentation of either the request for EPA 
confirmation or the letter of self-determination (or both, if 
applicable) along with all supporting documentation for the specific 
exemption listed in subpart E of this part.
    (b) Make the documentation outlined in paragraph (a) of this 
section available to EPA upon request.

0
8. Add subpart E to read as follows:
Subpart E--Exemption Eligibility Determination Process and Requirements
Sec.
174.90 Determining eligibility.
174.91 Submitting a letter of self-determination.
174.93 Requesting EPA confirmation.
174.95 Documentation for an exemption for a plant-incorporated 
protectant created through genetic engineering from a sexually 
compatible plant.
174.96 Documentation for an exemption for a loss-of-function plant-
incorporated protectant.

Subpart E--Exemption Eligibility Determination Process and 
Requirements


Sec.  174.90  Determining eligibility.

    (a) Options for determining eligibility. As required in Sec. Sec.  
174.21(d) and 174.541(c), the developer must notify EPA to be eligible 
for exemption. Available notification options differ by plant-
incorporated protectant. The developer must do at least one of the 
following:
    (1) EPA confirmation. Unless permitted in paragraph (a)(2) of this 
section, a developer must submit a request for EPA confirmation of 
eligibility in accordance with Sec.  174.93. Any developer may submit a 
request for EPA confirmation of eligibility in accordance with Sec.  
174.93.
    (2) Self-determination. A developer may submit a letter of self-
determination in accordance with Sec.  174.91 if the plant-incorporated 
protectant qualifies for exemption as one of the following:
    (i) A loss-of-function plant-incorporated protectant eligible for 
exemption under Sec.  174.27.
    (ii) [Reserved]
    (b) Where to submit a request for EPA confirmation or letter of 
self-determination. A request for EPA confirmation of eligibility or a 
letter of self-determination must be submitted electronically.
    (c) Claims of confidentiality. Any claims of confidentiality for 
information submitted in the request for EPA confirmation or a letter 
of self-determination must be made in accordance with the procedures 
outlined in Sec.  174.9.
    (d) Overlapping determinations of eligibility. If a plant-
incorporated protectant is eligible for a self-determination option, a 
developer may elect to submit a letter of self-determination as well as 
a request for EPA confirmation of eligibility concurrently or at a 
later time. If the developer so elects, the letter of self-
determination will remain in effect while EPA evaluates the request for 
confirmation of eligibility.

[[Page 34778]]

    (e) Revisiting eligibility determination. If, at any time after EPA 
issues a confirmation of eligibility or the letter of self-
determination is submitted, EPA becomes aware of information indicating 
that a plant-incorporated protectant no longer meets the criteria for 
exemption (e.g., adverse effects reports submitted under Sec.  174.71) 
or that the self-determination was incorrect, EPA will generally notify 
the submitter in writing of EPA's intention to initiate a review of 
eligibility for exemption and may request additional information from 
the submitter in order to evaluate that eligibility for exemption. Upon 
conclusion of its review, EPA will notify the submitter in writing of 
its determination as to whether the plant-incorporated protectant meets 
the exemption criteria and any actions that will be required should the 
plant-incorporated protectant be found to not meet the exemption 
criteria. Under those circumstances, the plant-incorporated protectant 
may be considered to be noncompliant with FIFRA and subject to possible 
enforcement by EPA. At any time, if EPA finds or has reason to believe 
that a plant-incorporated protectant's non-compliance with FIFRA 
requires immediate action, EPA may take such action, including 
enforcement, without first informing the submitter of an eligibility 
review.
    (f) Extension of exemption. An exemption can be extended in one of 
two ways. First, if the exempted plant-incorporated protectant is moved 
through conventional breeding to other plants, the exemption is 
extended to the subsequent plant-incorporated protectant. Second, to 
extend the exemption of the plant-incorporated protectant to subsequent 
genetic engineering events in other plants, the following exemption-
specific criteria apply:
    (1) Plant-incorporated protectant created through genetic 
engineering from a sexually compatible plant. An exemption extends to a 
plant-incorporated protectant when that plant-incorporated protectant 
is genetically engineered by the submitter into another variety of that 
same plant species, the substance produced is identical to the 
substance produced in the original recipient plant, and no new 
modifications were made to the regulatory regions.
    (2) Loss of function plant-incorporated protectant. An exemption 
extends to a plant-incorporated protectant when that plant-incorporated 
protectant is genetically engineered by the submitter into another 
variety of that same plant species and the same native gene is targeted 
to create the loss-of-function PIP.
    (g) No duplication necessary. A developer is not required to submit 
duplicative requests for eligibility determination or self-
determination under both Sec. Sec.  174.541(c) and 174.21(d), if it has 
already been submitted for purposes of determining eligibility under 
Sec.  174.21(d).


Sec.  174.91  Submitting a letter of self-determination.

    To self-determine eligibility for the exemption of a plant-
incorporated protectant listed under Sec.  174.90(a)(2), a developer 
must comply with all of the following requirements.
    (a) When to submit a letter of self-determination. A letter of 
self-determination for an exemption must be submitted to EPA prior to 
engaging in any activity that would be subject to FIFRA absent an 
exemption.
    (b) Contents of a letter of self-determination. The letter of self-
determination must:
    (1) Provide the name and contact information for the submitter 
(including telephone number and email address), company name, or other 
affiliation.
    (2) Identify the plant-incorporated protectant by providing: the 
identity of the recipient plant (genus and species), a unique 
identifier for the native gene from the National Center for 
Biotechnology Information (NCBI) at the National Library of Medicine of 
the National Institutes of Health (NLM) at the National Institutes of 
Health (NIH) (i.e., Entrez GeneID), the trait type (e.g., insect 
resistance), and cite the paragraph under Sec.  174.90(a)(2) that 
indicates that the plant-incorporated protectant is eligible for self-
determination.
    (3) Complete and submit the certification statement provided in the 
electronic submission portal. The statement must be dated and signed by 
the certifying official identified in the certification statement.
    (c) EPA response. EPA will provide electronic confirmation of 
receipt immediately. Electronic confirmation of receipt shall be 
equivalent to written confirmation of receipt.
    (d) Effective date of exemption. The exemption does not apply until 
EPA confirms receipt of the letter of self-determination.


Sec.  174.93  Requesting EPA confirmation.

    To request EPA confirmation of eligibility for exemption of a 
plant-incorporated protectant listed under Sec.  174.21(d), a developer 
must comply with all of the following requirements.
    (a) When to submit a request for EPA confirmation. Unless the 
developer has received confirmation of receipt of a letter of self-
determination, the request for EPA confirmation must be submitted prior 
to engaging in any activity that would be subject to FIFRA absent an 
exemption.
    (b) Contents of a request for EPA confirmation of exemption 
eligibility. The request must contain information as specified in Sec.  
174.91(b) and supporting documentation, as specified in exemption-
specific sections of this subpart (e.g., Sec.  174.95).
    (c) EPA review and response. Upon receipt of a request, EPA will 
review and evaluate the information provided to determine whether the 
plant-incorporated protectant meets the exemption criteria in Sec.  
174.21. EPA may require additional information to assess whether a 
plant-incorporated protectant meets the criteria for exemption. EPA 
will notify the submitter in writing of its determination. If EPA 
determines that the plant-incorporated protectant does not meet the 
criteria for exemption, EPA will notify the submitter in writing of any 
actions that will be required.
    (d) Effective date of exemption. If the plant-incorporated 
protectant is not already exempt pursuant to the self-determination 
process under Sec.  174.91, this exemption applies once EPA notifies 
the submitter in writing, confirming that the plant-incorporated 
protectant meets the criteria for exemption.


Sec.  174.95  Documentation for an exemption for a plant-incorporated 
protectant created through genetic engineering from a sexually 
compatible plant.

    A developer requesting EPA confirmation of exemption eligibility 
for a plant-incorporated protectant created through genetic engineering 
from a sexually compatible plant pursuant to Sec.  174.93 must submit 
the information in the following paragraphs to EPA. The following 
documentation must be maintained by a developer of a plant-incorporated 
protectant created through genetic engineering from a sexually 
compatible plant per Sec.  174.73:
    (a) Biology of the plant. (1) The identity of the recipient plant, 
including genus and species.
    (2) If the plant-incorporated protectant was derived from a plant 
species other than the recipient plant species, provide the identity of 
the source plant including genus and species and information to support 
the determination that the recipient plant and the source plant are 
sexually compatible (e.g., through peer-reviewed literature rationale).
    (b) Description of the pesticidal trait and how the trait was 
engineered into

[[Page 34779]]

the plant. Include a description of the measures that were taken to 
ensure that no engineering components (e.g., Cas proteins) are present 
in the final plant product and the measures taken to maximize the 
likelihood that the modification to the recipient plant is limited to 
the intended modification.
    (c) Molecular characterization of the plant-incorporated 
protectant. A nucleic acid sequence comparison of the plant-
incorporated protectant between the recipient plant and the 
comparator(s). A deduced amino acid sequence comparison is additionally 
required when the pesticidal substance is proteinaceous. The relevant 
comparator(s) for the sequence comparison(s) are determined by the type 
of modification:
    (1) For Sec.  174.26(a)(1), sequences in the source plant and in 
the recipient plant.
    (2) For Sec.  174.26(a)(2), sequences in the recipient plant before 
the modification, after the modification, and the sequence in the 
source plant. The polymorphic site(s) must be indicated.
    (d) Information on the history of safe use of the plant-
incorporated protectant. (1) If the pesticidal substance is a known 
allergen or mammalian toxin/toxicant (e.g., solanine), describe how 
conventional breeding practices are being used to ensure that it does 
not exceed human dietary safety levels in the recipient food plant 
(i.e., ensure residues of pesticidal substance are not present in food 
at levels that are injurious or deleterious and are within the ranges 
of levels generally seen in plant varieties currently on the market 
and/or known to produce food safe for consumption).
    (2) If the source plant is a wild relative of the recipient plant, 
describe why the plant-incorporated protectant is not anticipated to 
pose a hazard to humans or the environment (e.g., Are levels of the 
pesticidal substance produced in the recipient plant within the ranges 
of levels generally seen in plant varieties currently on the market 
and/or known to produce food safe for consumption? Is the pesticidal 
mode of action non-toxic? Does the plant-incorporated protectant lack 
sequence similarity to known mammalian toxins, toxicants, or allergens? 
Is the plant-incorporated protectant a commonly screened substance and 
therefore familiar to plant breeders?).


Sec.  174.96  Documentation for an exemption for a loss-of-function 
plant-incorporated protectant.

    A developer requesting EPA confirmation of exemption eligibility 
for a loss-of-function plant-incorporated protectant pursuant to Sec.  
174.93 must submit the information in the following paragraphs to EPA 
along with the developer's request for exemption confirmation. The 
following documentation must be maintained by a developer of a loss-of-
function plant-incorporated protectant per Sec.  174.73:
    (a) Biology of the plant: The identity of the recipient plant, 
including genus and species.
    (b) Description of the pesticidal trait that results from the loss-
of-function and how the trait was engineered into the plant. Include a 
description of the steps that were taken to ensure that no engineering 
components (e.g., Cas proteins) remain in the plant and the measures 
taken to maximize the likelihood that the modification to the recipient 
plant is limited to the intended modification.

0
9. Amend Sec.  174.508 by:
0
a. Revising the section heading and introductory text;
0
b. Redesignating paragraph (c) as paragraph (d); and
0
c. Adding a new paragraph (c).
    These revisions and addition read as follows:


Sec.  174.508  Pesticidal substance of a plant-incorporated protectant 
from a sexually compatible plant created through conventional breeding; 
exemption from the requirement of a tolerance.

    Residues of a pesticidal substance are exempt from the requirement 
of a tolerance if all the following conditions are met:
* * * * *
    (c) The genetic material is transferred from the source plant to 
the recipient plant only through conventional breeding.
* * * * *

0
10. Add Sec.  174.541 to read as follows:


Sec.  174.541  Pesticidal substance of a plant-incorporated protectant 
created through genetic engineering from a sexually compatible plant; 
exemption from the requirement of a tolerance.

    Residues of a pesticidal substance are exempt from the requirements 
of a tolerance if the conditions in paragraphs (a) through (c) of this 
section are met.
    (a) The pesticidal substance is characteristic of the population of 
plants sexually compatible with the recipient food plant and is created 
through genetic engineering from either an insertion of a native gene 
into the recipient food plant as specified in paragraph (a)(1) of this 
section or a modification of an existing native gene in the recipient 
food plant as specified in paragraph (a)(2) of this section.
    (1) Insertion. A native gene is inserted into the genome of the 
recipient food plant and produces a pesticidal substance identical in 
sequence to the pesticidal substance identified in the source plant. 
The regulatory regions inserted as part of the native gene must be 
identical in nucleic acid sequence to those regulatory regions of the 
native gene identified in the source plant.
    (2) Modification. The existing native gene is modified to match 
corresponding polymorphic sequence(s) in a native allele of that gene 
using a single source plant as a template.
    (b) The residues of the pesticidal substance are not present in 
food from the plant at levels that are injurious or deleterious to 
human health.
    (c) This exemption does not apply until the requirements in Sec.  
174.90 have been met.

[FR Doc. 2023-11477 Filed 5-30-23; 8:45 am]
BILLING CODE 6560-50-P


